Is ITGAL p.Pro976Ser (c.2926C>T) pathogenic?

ITGAL p.Pro976Ser (c.2926C>T) is classified Uncertain significance in ITGAL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.2789); Very rare (popmax 0.00161%, nfe).

How common is ITGAL p.Pro976Ser (c.2926C>T) in the general population?

ITGAL p.Pro976Ser (c.2926C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about ITGAL p.Pro976Ser (c.2926C>T)?

AlphaMissense predicts likely benign (score 0.2789) — an in-silico prediction, not a clinical call.

ITGAL p.Pro976Ser

c.2926C>T · VCV4088395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2789	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -6.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.86, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.00072 · regional, not allelic
Overall
CADD	20.7	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 0.00161% European (non-Finnish) · 19/1,179,626 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00137% 20/1,461,232 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,086
South Asian	0.0011%	91,052

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: ITGAL
Protein: p.Pro976Ser
Coding: c.2926C>T
MANE Select: NM_002209
Type: single nucleotide variant
Location: chr16:30517036 (GRCh38)
Gene constraint: LOEUF 0.595 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.77 · 41 PDB

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

Similar variants

ITGAL c.1213+9T>G Benign ★★ same type
ITGAL p.Ala307= Benign ★★ same type
ITGAL p.Arg1020His Benign/Likely benign ★★ ⚠ same type
ITGAL p.Pro1152= Benign ★★ same type
ITGAL p.Ser891= Benign ★★ same type
ITGAL p.Ala1045Pro Uncertain significance ★ ⚠ same type
ITGAL p.Ala1072Thr Uncertain significance ★ ⚠ same type
ITGAL p.Ala1127Pro Uncertain significance ★ ⚠ same type

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/itgal-p-pro976ser (accessed [today's date]).

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