Is IFT122 p.Ser264Phe (c.791C>T) pathogenic?

IFT122 p.Ser264Phe (c.791C>T) is classified Uncertain significance in IFT122 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.8736); Very rare (popmax 0.00133%, afr); Associated with cranioectodermal dysplasia 1.

What condition is associated with IFT122 p.Ser264Phe (c.791C>T)?

IFT122 p.Ser264Phe (c.791C>T) is associated with cranioectodermal dysplasia 1 (ClinVar).

How common is IFT122 p.Ser264Phe (c.791C>T) in the general population?

IFT122 p.Ser264Phe (c.791C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about IFT122 p.Ser264Phe (c.791C>T)?

AlphaMissense predicts likely pathogenic (score 0.8736) — an in-silico prediction, not a clinical call.

IFT122 p.Ser264Phe

c.791C>T · VCV3588410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cranioectodermal dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.8736	likely pathogenic
REVEL	0.545	indeterminate
SaProt	LLR -11.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 25 kb · p 4.4e-05 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,054 alleles

Overall 0.000186% 3/1,614,014 alleles · very rare exomes 3/1,461,692 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
African / African-Americangrpmax	0.00133%	75,054
European (non-Finnish)	8.48e-05%	1,179,935

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: IFT122
Protein: p.Ser264Phe
Coding: c.791C>T
MANE Select: NM_052989
Type: single nucleotide variant
Location: chr3:129469392 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.91 · 5 PDB
Residue 264: a β-strand

Full IFT122 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cranioectodermal dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IFT122 c.1148-1G>C Pathogenic/Likely pathogenic ★★ same condition
IFT122 c.272+1G>A Likely pathogenic ★★ same condition
IFT122 c.273-257C>A Pathogenic/Likely pathogenic ★★ same condition
IFT122 c.3265+1G>A Pathogenic/Likely pathogenic ★★ same condition
IFT122 p.Arg1185Ter Pathogenic/Likely pathogenic ★★ same condition
IFT122 p.Arg189Ter Pathogenic/Likely pathogenic ★★ same condition
IFT122 p.Arg673Ter Pathogenic/Likely pathogenic ★★ same condition
IFT122 p.Gln1005Ter Pathogenic ★★ same condition

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/ift122-p-ser264phe (accessed [today's date]).

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