Is ITGAL p.Pro994Ser (c.2980C>T) pathogenic?

ITGAL p.Pro994Ser (c.2980C>T) is classified Uncertain significance in ITGAL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.1614); Very rare (popmax 0.00223%, eas).

How common is ITGAL p.Pro994Ser (c.2980C>T) in the general population?

ITGAL p.Pro994Ser (c.2980C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ITGAL p.Pro994Ser (c.2980C>T)?

AlphaMissense predicts likely benign (score 0.1614) — an in-silico prediction, not a clinical call.

ITGAL p.Pro994Ser

c.2980C>T · rs1567492105 · VCV2623080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1614	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -12.59	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.47, phastCons 0.76
Regional constraint	o/e 0.89	unconstrained · MANE · 32 kb · p 0.00072 · regional, not allelic
Overall
CADD	13.22	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 0.00223% East Asian · 1/44,878 alleles

Overall 6.2e-05% 1/1,613,814 alleles · very rare exomes 1/1,461,564 · genomes 0/152,250 · joint denominator

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.Pro994Ser
Coding: c.2980C>T
MANE Select: NM_002209
dbSNP: rs1567492105
Type: single nucleotide variant
Location: chr16:30517652 (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-pro994ser (accessed [today's date]).

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