FAHD1

Chr 16

FAH domain containing oxaloacetate decarboxylase 1

Also known as: C16orf36, ODx, YISKL

NCBI Gene: 81889 ENSG00000180185 UniProt: Q6P587 OMIM: 616320

The FAHD1 protein functions as a tautomerase that converts inhibitory enol-oxaloacetate to keto-oxaloacetate, preventing succinate dehydrogenase inhibition and maximizing aerobic respiration efficiency, and also acts as a weak oxaloacetase in the TCA cycle. Biallelic mutations cause autosomal recessive early-onset mitochondrial encephalomyopathy with lactic acidosis. The gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Enables hydrolase activity, acting on acid carbon-carbon bonds, in ketonic substances; oxaloacetate decarboxylase activity; and oxaloacetate tautomerase activity. Involved in oxaloacetate metabolic process. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.97

Clinical Summary— FAHD1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 60 VUS of 77 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.97LOEUF

pLI 0.000

Z-score -2.29

OE 1.91 (1.15–1.97)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.84Z-score

OE missense 1.44 (1.28–1.62)

198 obs / 137.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.91 (1.15–1.97)

0≤0.351.4

Missense OE?1.44 (1.28–1.62)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 14 / 7.3Missense obs/exp: 198 / 137.3Syn Z: -1.71

This gene — mechanism propensity

0.5869th %ile

GOF

0.6444th %ile

LOF

0.4430th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

LOF80% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

77 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS60

Likely Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	1	3
Likely Pathogenic	2	0	0	0	2
VUS	0	60	0	0	60
Likely Benign	0	1	1	0	2
Benign	0	0	0	0	0
Total	4	61	1	1	67

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap FAHD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →