Is ITGA4 p.Ser628Pro (c.1882T>C) pathogenic?

ITGA4 p.Ser628Pro (c.1882T>C) is classified Uncertain significance in ITGA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.4733); Very rare (popmax 0.00205%, nfe).

How common is ITGA4 p.Ser628Pro (c.1882T>C) in the general population?

ITGA4 p.Ser628Pro (c.1882T>C) is very rare (popmax 0.00205%, nfe) (gnomAD).

What do computational predictors say about ITGA4 p.Ser628Pro (c.1882T>C)?

AlphaMissense predicts ambiguous (score 0.4733) — an in-silico prediction, not a clinical call.

ITGA4 p.Ser628Pro

c.1882T>C · rs200238285 · VCV3111227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4733	ambiguous
REVEL	0.249	benign-leaning
SaProt	LLR -5.84	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.66, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 32 kb · p 0.006 · regional, not allelic
Overall
CADD	23.8	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 0.00205% European (non-Finnish) · 24/1,168,012 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00117%

Overall 0.00162% 26/1,600,224 alleles · very rare exomes 23/1,448,136 · genomes 3/152,088 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00205%	48,667
Admixed American	0.00167%	59,876
Remaining individualsnot grpmax-eligible	0.00161%	61,956

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: ITGA4
Protein: p.Ser628Pro
Coding: c.1882T>C
MANE Select: NM_000885
dbSNP: rs200238285
Type: single nucleotide variant
Location: chr2:181511735 (GRCh38)
Gene constraint: LOEUF 0.603 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 84.11 · 7 PDB

Full ITGA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ITGA4 c.1042-6A>G Benign ★★ same type
ITGA4 c.2884-7C>G Likely benign ★★ same type
ITGA4 c.754+10A>C Benign ★★ same type
ITGA4 c.841-15T>C Benign ★★ same type
ITGA4 p.Ser634Thr Benign ★★ same type
ITGA4 c.*2719T>C Likely pathogenic ★ same type
CERKL c.*1212A>G Uncertain significance ★ same type
CERKL c.*25G>T 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/itga4-p-ser628pro (accessed [today's date]).

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