Is BCAR3 p.Arg595Cys (c.1783C>T) pathogenic?

BCAR3 p.Arg595Cys (c.1783C>T) is classified Uncertain significance in BCAR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely pathogenic (0.7648); Very rare (popmax 0.00133%, afr).

How common is BCAR3 p.Arg595Cys (c.1783C>T) in the general population?

BCAR3 p.Arg595Cys (c.1783C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BCAR3 p.Arg595Cys (c.1783C>T)?

AlphaMissense predicts likely pathogenic (score 0.7648) — an in-silico prediction, not a clinical call.

BCAR3 p.Arg595Cys

c.1783C>T · rs776773073 · VCV2556583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7648 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7648	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -14.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 113 kb · p 0.0058 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/75,020 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000752% 11/1,461,852 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00156%	64,034
African / African-Americangrpmax	0.00133%	75,020
European (non-Finnish)	0.000593%	168,571

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BCAR3
Protein: p.Arg595Cys
Coding: c.1783C>T
MANE Select: NM_003567
dbSNP: rs776773073
Type: single nucleotide variant
Location: chr1:93576033 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.36 · 1 PDB
Residue 595: the ras-gef domain; an α-helix

Full BCAR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAR3 p.Arg758Gln Uncertain significance ★★ ⚠ same type
BCAR3 p.Asn733Ser Benign ★★ same type
BCAR3 p.Thr506= Benign ★★ same type
BCAR3 p.Ala196Ser Uncertain significance ★ ⚠ same type
BCAR3 p.Ala196Thr Uncertain significance ★ ⚠ same type
BCAR3 p.Ala211Asp Uncertain significance ★ ⚠ same type
BCAR3 p.Ala247Thr Uncertain significance ★ ⚠ same type
BCAR3 p.Ala391Val 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/bcar3-p-arg595cys (accessed [today's date]).

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