Is IFT80 p.Arg253Cys (c.757C>T) pathogenic?

IFT80 p.Arg253Cys (c.757C>T) is classified Uncertain significance in IFT80 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely benign (0.221); Ultra-rare (popmax 0.0165%, mid); Associated with Jeune syndrome.

What condition is associated with IFT80 p.Arg253Cys (c.757C>T)?

IFT80 p.Arg253Cys (c.757C>T) is associated with Jeune syndrome (ClinVar).

How common is IFT80 p.Arg253Cys (c.757C>T) in the general population?

IFT80 p.Arg253Cys (c.757C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about IFT80 p.Arg253Cys (c.757C>T)?

AlphaMissense predicts likely benign (score 0.221) — an in-silico prediction, not a clinical call.

IFT80 p.Arg253Cys

c.757C>T · rs138656118 · VCV1499720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.221	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -15.25	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.82, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 126 kb · p 0.00011 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00477% 77/1,614,064 alleles · ultra-rare exomes 77/1,461,736 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.0061%	16,389
East Asian	0.00223%	44,874
South Asian	0.0022%	45,540
African / African-American	0.00133%	75,044

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: IFT80
Protein: p.Arg253Cys
Coding: c.757C>T
MANE Select: NM_020800
dbSNP: rs138656118
Type: single nucleotide variant
Location: chr3:160356033 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.50

Full IFT80 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

IFT80 p.Arg253= Likely benign ★ same residue
IFT80 p.Arg253Leu Uncertain significance ★ same residue
IFT80 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
IFT80 p.Trp155Ter Pathogenic/Likely pathogenic ★★ same condition
IFT80 c.1076+6C>A Uncertain significance ★★ same condition
IFT80 c.1836+5T>C Uncertain significance ★★ same condition
IFT80 c.370+6T>C Uncertain significance ★★ same condition
IFT80 p.Ala154Val Uncertain significance ★★ ⚠ 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/ift80-p-arg253cys (accessed [today's date]).

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