Is BCAS2 p.Met127Val (c.379A>G) pathogenic?

BCAS2 p.Met127Val (c.379A>G) is classified Uncertain significance in BCAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-13). AlphaMissense: likely pathogenic (0.7512); Very rare (popmax 0.00119%, nfe).

How common is BCAS2 p.Met127Val (c.379A>G) in the general population?

BCAS2 p.Met127Val (c.379A>G) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about BCAS2 p.Met127Val (c.379A>G)?

AlphaMissense predicts likely pathogenic (score 0.7512) — an in-silico prediction, not a clinical call.

BCAS2 p.Met127Val

c.379A>G · rs1037770890 · VCV2469191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7512	likely pathogenic
REVEL	0.634	indeterminate
SaProt	LLR -10.97	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 13 kb · p 0.004 · regional, not allelic
Overall
CADD	22.3	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 0.00119% European (non-Finnish) · 14/1,179,794 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000931% 15/1,611,882 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,292
European (non-Finnish)grpmax	0.00119%	84,271

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: BCAS2
Protein: p.Met127Val
Coding: c.379A>G
MANE Select: NM_005872
dbSNP: rs1037770890
Type: single nucleotide variant
Location: chr1:114575630 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.36 · 26 PDB
Residue 127: an α-helix

Full BCAS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAS2 p.Ala2Val Uncertain significance ★ ⚠ same type
BCAS2 p.Ala75Val Uncertain significance ★ ⚠ same type
BCAS2 p.Arg222Gln Uncertain significance ★ ⚠ same type
BCAS2 p.Arg76Gln Uncertain significance ★ ⚠ same type
BCAS2 p.Asn123Thr Uncertain significance ★ ⚠ same type
BCAS2 p.Asn133Ser Uncertain significance ★ ⚠ same type
BCAS2 p.Asn220Asp Uncertain significance ★ ⚠ same type
BCAS2 p.Asn48Ser 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/bcas2-p-met127val (accessed [today's date]).

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