Is IFT172 p.Val33Ala (c.98T>C) pathogenic?

IFT172 p.Val33Ala (c.98T>C) is classified Conflicting classifications of pathogenicity in IFT172 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-28). AlphaMissense: likely pathogenic (0.5898); Ultra-rare (popmax 0.0165%, mid); Associated with short-rib thoracic dysplasia 10 with or without polydactyly.

How common is IFT172 p.Val33Ala (c.98T>C) in the general population?

IFT172 p.Val33Ala (c.98T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about IFT172 p.Val33Ala (c.98T>C)?

AlphaMissense predicts likely pathogenic (score 0.5898) — an in-silico prediction, not a clinical call.

IFT172 p.Val33Ala

Q: What condition is associated with IFT172 p.Val33Ala (c.98T>C)?

IFT172 p.Val33Ala (c.98T>C) is associated with short-rib thoracic dysplasia 10 with or without polydactyly, retinitis pigmentosa 71 (ClinVar).

c.98T>C · rs200884031 · VCV719920

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

short-rib thoracic dysplasia 10 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.5898	likely pathogenic
REVEL	0.493	indeterminate
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 32 kb · p 0.013 · regional, not allelic
Overall
CADD	25.8	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 · 1/6,076 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00892% 144/1,614,024 alleles · ultra-rare exomes 122/1,461,812 · genomes 22/152,212 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.334%	299
Remaining individualsnot grpmax-eligible	0.0288%	3,472
Middle Easterngrpmax	0.0165%	6,076
Admixed American	0.00667%	15,001
European (non-Finnish)	0.00178%	56,191
African / African-American	0.00133%	74,910

Ashkenazi Jewish 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: IFT172
Protein: p.Val33Ala
Coding: c.98T>C
MANE Select: NM_015662
dbSNP: rs200884031
Type: single nucleotide variant
Location: chr2:27485445 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.98 · 1 PDB

Full IFT172 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 10 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 71

Similar variants

IFT172 p.Val33Leu Uncertain significance ★ ⚠ same residue
IFT172 p.Val33= Likely benign ★ same residue
IFT172 c.1411+2T>C Likely pathogenic ★★ same condition
IFT172 c.1525-1G>A Pathogenic/Likely pathogenic ★★ same condition
IFT172 c.184-2A>C Likely pathogenic ★★ same condition
IFT172 c.2443-1G>C Likely pathogenic ★★ same condition
IFT172 c.2976-2A>T Likely pathogenic ★★ same condition
IFT172 c.3111+1G>T Likely 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/ift172-p-val33ala (accessed [today's date]).

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