Is BCAR1 p.Pro375Ser (c.1123C>T) pathogenic?

BCAR1 p.Pro375Ser (c.1123C>T) is classified Uncertain significance in BCAR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.6636); Very rare (popmax 0.00228%, sas).

How common is BCAR1 p.Pro375Ser (c.1123C>T) in the general population?

BCAR1 p.Pro375Ser (c.1123C>T) is very rare (popmax 0.00228%, sas) (gnomAD).

What do computational predictors say about BCAR1 p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely pathogenic (score 0.6636) — an in-silico prediction, not a clinical call.

BCAR1 p.Pro375Ser

c.1123C>T · VCV3990881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6636	likely pathogenic
REVEL	0.246	benign-leaning
SaProt	LLR -11.81	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 13 kb · p 6.7e-05 · regional, not allelic
Overall
CADD	26.1	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 0.00228% South Asian · 2/87,752 alleles

Filtering AF 0.00081% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000656%

Overall 0.00113% 18/1,592,622 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00228%	43,876
European (non-Finnish)	0.00137%	73,037

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: BCAR1
Protein: p.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_014567
Type: single nucleotide variant
Location: chr16:75235776 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.07 · 5 PDB
Residue 375: the 'substrate for kinases' region

Full BCAR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAR1 c.2100+10C>T Benign/Likely benign ★★ same type
BCAR1 p.Ala411= Benign ★★ same type
BCAR1 p.Ala514= Benign ★★ same type
BCAR1 p.Ala590Thr Benign ★★ ⚠ same type
BCAR1 p.Arg491Leu Benign ★★ same type
BCAR1 p.Gly450Val Benign ★★ same type
BCAR1 p.Gly568Ser Benign ★★ same type
BCAR1 p.His558Arg Benign ★★ 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/bcar1-p-pro375ser (accessed [today's date]).

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