AHDC1

Chr 1AD

AT-hook DNA binding motif containing 1

Also known as: MRD25, XIGIS

NCBI Gene: 27245ENSG00000126705UniProt: Q5TGY3

This gene encodes a protein containing two AT-hooks, which likely function in DNA binding. Mutations in this gene were found in individuals with Xia-Gibbs syndrome. [provided by RefSeq, Jun 2014]

Primary Disease Associations & Inheritance

Xia-Gibbs syndromeMIM #615829
AD
587
ClinVar variants
63
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— AHDC1
🧬
Gene-Disease Validity (ClinGen)
AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
63 Pathogenic / Likely Pathogenic· 328 VUS of 587 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.08LOEUF
pLI 1.000
Z-score 5.78
OE 0.00 (0.00–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.86Z-score
OE missense 0.75 (0.70–0.79)
764 obs / 1021.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.70–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 0 / 38.9Missense obs/exp: 764 / 1021.1Syn Z: -0.57

ClinVar Variant Classifications

587 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic19
VUS328
Likely Benign178
Benign5
Conflicting13
44
Pathogenic
19
Likely Pathogenic
328
VUS
178
Likely Benign
5
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
32
0
12
0
44
Likely Pathogenic
13
3
3
0
19
VUS
6
313
9
0
328
Likely Benign
0
39
0
139
178
Benign
0
2
0
3
5
Conflicting
—13
Total5135724142587

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

AHDC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

AHDC1-related Xia-Gibbs syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Xia-Gibbs syndrome

MIM #615829

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — AHDC1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ahdc1 is a potent regulator of obesity and energy metabolism.
Li L et al.·Am J Physiol Endocrinol Metab
2023
Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.
Khayat MM et al.·Hum Mutat
2021
Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review.
Romano F et al.·Birth Defects Res
2022Review
Clinical and Molecular Characterization of Xia-Gibbs Syndrome: Expanding the Phenotypic Spectrum in a Brazilian Cohort.
Sennes MGS et al.·Clin Genet
2025Cohort
The phenotypic spectrum of Xia-Gibbs syndrome.
Jiang Y et al.·Am J Med Genet A
2018
Exome-Based Rare-Variant Analyses in CKD.
Cameron-Christie S et al.·J Am Soc Nephrol
2019
[Analysis of a case with Xia-Gibbs syndrome due to variant of AHDC1 gene].
Fan L et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2022
Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis.
Jiang N et al.·Eur J Hum Genet
2025Review
Genetic investigation of syndromic forms of obesity.
Carvalho LML et al.·Int J Obes (Lond)
2022
Clinical presentation and evolution of Xia-Gibbs syndrome due to p.Gly375ArgfsTer3 variant in a patient from DR Congo (Central Africa).
Mubungu G et al.·Am J Med Genet A
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools