Is ITGA6 p.Pro366Ser (c.1096C>T) pathogenic?

ITGA6 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in ITGA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: ambiguous (0.5102); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with ITGA6 p.Pro366Ser (c.1096C>T)?

ITGA6 p.Pro366Ser (c.1096C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITGA6 p.Pro366Ser (c.1096C>T) in the general population?

ITGA6 p.Pro366Ser (c.1096C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about ITGA6 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts ambiguous (score 0.5102) — an in-silico prediction, not a clinical call.

ITGA6 p.Pro366Ser

c.1096C>T · VCV3530398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5102 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5102	ambiguous
REVEL	0.483	indeterminate
SaProt	LLR -9.28	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 5.9e-11 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P405S vs ClinVar P366S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,014 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000187% 3/1,606,296 alleles · very rare exomes 3/1,454,096 · genomes 0/152,200 · 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: ITGA6
Protein: p.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_000210
Type: single nucleotide variant
Location: chr2:172475038 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.69 (gnomAD)
Structure: AlphaFold pLDDT 80.05 · 2 PDB
Residue 405 UniProt numbering: an α-helix

Full ITGA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ITGA6 p.Pro366Thr Uncertain significance ★ same residue
ITGA6 p.Ala1024Thr Uncertain significance ★★ ⚠ same condition
ITGA6 p.Ala491Val Uncertain significance ★★ ⚠ same condition
ITGA6 p.Ala90Thr Uncertain significance ★★ ⚠ same condition
ITGA6 p.Arg19Trp Uncertain significance ★★ ⚠ same condition
ITGA6 p.Arg484His Uncertain significance ★★ ⚠ same condition
ITGA6 p.Arg578His Uncertain significance ★★ ⚠ same condition
ITGA6 p.Arg902Gln 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/itga6-p-pro366ser (accessed [today's date]).

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