Is BCAS4 p.Val141Met (c.421G>A) pathogenic?

BCAS4 p.Val141Met (c.421G>A) is classified Uncertain significance in BCAS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.1092); Ultra-rare (popmax 0.0329%, mid).

How common is BCAS4 p.Val141Met (c.421G>A) in the general population?

BCAS4 p.Val141Met (c.421G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about BCAS4 p.Val141Met (c.421G>A)?

AlphaMissense predicts likely benign (score 0.1092) — an in-silico prediction, not a clinical call.

BCAS4 p.Val141Met

c.421G>A · rs367775804 · VCV3133339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1092 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1092	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -2.7
Regional constraint	o/e 0.94	unconstrained · MANE · 82 kb · p 0.36 · regional, not allelic
Overall
CADD	0.738	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R203H vs ClinVar V141M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00589% 95/1,613,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
East Asian	0.0312%	3,205
African / African-American	0.0187%	5,346
Remaining individualsnot grpmax-eligible	0.0096%	10,412
Admixed American	0.005%	19,982
European (non-Finnish)	0.00449%	22,262
South Asian	0.00329%	30,349

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: BCAS4
Protein: p.Val141Met
Coding: c.421G>A
MANE Select: NM_198799
dbSNP: rs367775804
Type: single nucleotide variant
Location: chr20:50876507 (GRCh38)
Gene constraint: LOEUF 1.081 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.40

Full BCAS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAS4 p.Ser130Thr Benign ★★ same type
BCAS4 p.Ser130Tyr Benign/Likely benign ★★ ⚠ same type
BCAS4 p.Thr142Met Likely benign ★★ same type
BCAS4 c.-15C>T Uncertain significance ★ ⚠ same type
BCAS4 c.-6C>T Uncertain significance ★ ⚠ same type
BCAS4 p.Ala118Ser Uncertain significance ★ ⚠ same type
BCAS4 p.Ala126Thr Uncertain significance ★ ⚠ same type
BCAS4 p.Ala29Ser 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/bcas4-p-val141met (accessed [today's date]).

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