Is IFT80 p.Val646Phe (c.1936G>T) pathogenic?

IFT80 p.Val646Phe (c.1936G>T) is classified Uncertain significance in IFT80 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-18). AlphaMissense: likely pathogenic (0.7875); Ultra-rare (popmax 0.01%, amr); Associated with Jeune syndrome.

What condition is associated with IFT80 p.Val646Phe (c.1936G>T)?

IFT80 p.Val646Phe (c.1936G>T) is associated with Jeune syndrome, asphyxiating thoracic dystrophy 2 (ClinVar).

How common is IFT80 p.Val646Phe (c.1936G>T) in the general population?

IFT80 p.Val646Phe (c.1936G>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about IFT80 p.Val646Phe (c.1936G>T)?

AlphaMissense predicts likely pathogenic (score 0.7875) — an in-silico prediction, not a clinical call.

IFT80 p.Val646Phe

c.1936G>T · rs752617502 · VCV1025611

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7875 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.7875	likely pathogenic
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -12.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 126 kb · p 0.00011 · 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 0.01% Admixed American · 6/59,808 alleles

Filtering AF 0.00474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00434%

Overall 0.00537% 86/1,602,740 alleles · ultra-rare exomes 81/1,450,862 · genomes 5/151,878 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,968
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,764
European (non-Finnish)	0.00589%	16,965
South Asian	0.00441%	22,673
African / African-American	0.00403%	24,798
Remaining individualsnot grpmax-eligible	0.00322%	31,048

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.Val646Phe
Coding: c.1936G>T
MANE Select: NM_020800
dbSNP: rs752617502
Type: single nucleotide variant
Location: chr3:160277469 (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

Also linked: asphyxiating thoracic dystrophy 2

Similar variants

IFT80 p.Val646Ile 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 c.*108A>G 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-val646phe (accessed [today's date]).

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