IFT57

Chr 3AR

intraflagellar transport 57

Also known as: ESRRBL1, HIPPI, MHS4R2, OFD18

NCBI Gene: 55081 ENSG00000114446 UniProt: Q9NWB7 OMIM: 606621

IFT57 encodes a protein required for cilia formation and plays a role in sonic hedgehog signaling and localization of specific G protein-coupled receptors to primary cilia. Biallelic mutations cause orofaciodigital syndrome XVIII, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants, with a very low pLI score and LOEUF of 1.096.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable DNA binding activity. Acts upstream of or within apoptotic process and regulation of apoptotic process. Located in ciliary base and photoreceptor connecting cilium. Part of intraciliary transport particle B. Implicated in orofaciodigital syndrome XVIII. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.101 OMIM phenotype

Clinical Summary— IFT57

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Gene-Disease Validity (ClinGen)

ciliopathy · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

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

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 152 VUS of 273 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?

1.10LOEUF

pLI 0.000

Z-score 1.19

OE 0.74 (0.51–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.30Z-score

OE missense 0.94 (0.84–1.06)

217 obs / 229.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.51–1.10)

0≤0.351.4

Missense OE?0.94 (0.84–1.06)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 18 / 24.4Missense obs/exp: 217 / 229.9Syn Z: -0.16

This gene — mechanism propensity

0.6355th %ile

GOF

0.5367th %ile

LOF

0.3551th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS152

Likely Benign85

Benign19

Conflicting2

Pathogenic

Likely Pathogenic

152

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	1	1
Likely Pathogenic	1	0	1	0	2
VUS	18	121	13	0	152
Likely Benign	0	5	41	39	85
Benign	0	3	8	8	19
Conflicting	—				2
Total	19	129	63	48	261

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap IFT57 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →