Is IFT74 p.Ser32Pro (c.94T>C) pathogenic?

IFT74 p.Ser32Pro (c.94T>C) is classified Uncertain significance in IFT74 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-07). AlphaMissense: likely benign (0.0652); Ultra-rare (popmax 0.0495%, mid); Associated with Bardet-Biedl syndrome 22.

What condition is associated with IFT74 p.Ser32Pro (c.94T>C)?

IFT74 p.Ser32Pro (c.94T>C) is associated with Bardet-Biedl syndrome 22 (ClinVar).

How common is IFT74 p.Ser32Pro (c.94T>C) in the general population?

IFT74 p.Ser32Pro (c.94T>C) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about IFT74 p.Ser32Pro (c.94T>C)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

IFT74 p.Ser32Pro

c.94T>C · rs201259858 · VCV1028870

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bardet-Biedl syndrome 22

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 101 kb · p 1.9e-05 · regional, not allelic
Overall
CADD	18.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00062% 10/1,614,156 alleles · ultra-rare exomes 10/1,461,860 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
African / African-American	0.00533%	18,760
Remaining individualsnot grpmax-eligible	0.0032%	31,252
East Asian	0.00223%	44,870

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: IFT74
Protein: p.Ser32Pro
Coding: c.94T>C
MANE Select: NM_025103
dbSNP: rs201259858
Type: single nucleotide variant
Location: chr9:26962061 (GRCh38)
Gene constraint: LOEUF 1.508 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.21
Residue 32: the 'basic region' region; the 'disordered' region; a UniProt-annotated variant site (in jbts40)

Full IFT74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome 22 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

IFT74 c.1685-1G>T Pathogenic/Likely pathogenic ★★ same condition
IFT74 p.Glu120Ter Pathogenic/Likely pathogenic ★★ same condition
IFT74 p.Arg448His Uncertain significance ★★ ⚠ same condition
IFT74 p.Ile498Val Uncertain significance ★★ ⚠ same condition
IFT74 p.Ile55Met Benign ★★ same condition
IFT74 p.Lys85Arg Benign ★★ same condition
IFT74 p.Thr597Ile Benign ★★ same condition
IFT74 c.974+1G>A 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/ift74-p-ser32pro (accessed [today's date]).

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