Is IFT57 p.Lys259= (c.777G>A) pathogenic?

IFT57 p.Lys259= (c.777G>A) is classified Pathogenic in IFT57 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-09). Very rare (popmax 0.00189%, amr); Associated with orofaciodigital syndrome 18.

What condition is associated with IFT57 p.Lys259= (c.777G>A)?

IFT57 p.Lys259= (c.777G>A) is associated with orofaciodigital syndrome 18 (ClinVar).

How common is IFT57 p.Lys259= (c.777G>A) in the general population?

IFT57 p.Lys259= (c.777G>A) is very rare (popmax 0.00189%, amr) (gnomAD).

IFT57 p.Lys259=

c.777G>A · rs1553741312 · VCV506288

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00189%, amr)

Conditions

orofaciodigital syndrome 18

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.78	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.77	loss · gain 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00189% Admixed American · 1/52,814 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000319% 5/1,569,278 alleles · very rare exomes 5/1,419,328 · genomes 0/149,950 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00189%	52,814
African / African-American	0.00139%	72,132
South Asian	0.00122%	81,952
European (non-Finnish)	0.000172%	580,390

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IFT57
Protein: p.Lys259=
Coding: c.777G>A
MANE Select: NM_018010
dbSNP: rs1553741312
Type: single nucleotide variant
Location: chr3:108191521 (GRCh38)
Gene constraint: LOEUF 1.425 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.92

Full IFT57 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

orofaciodigital syndrome 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IFT57 c.585+3A>G Likely pathogenic ★★ same condition
IFT57 c.375+17C>G Benign ★★ same condition
IFT57 p.Met390Val Uncertain significance ★ ⚠ same condition
IFT57 p.Ala155Ser Uncertain significance ⚠ same condition
IFT57 p.Thr294fs Likely pathogenic ★ same condition
IFT57 c.981+4A>G Uncertain significance ★★ same type
IFT57 p.Ala155Thr Uncertain significance ★★ ⚠ same type
IFT57 p.Ala37Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ift57-p-lys259 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown