Is BCAS4 p.Met77Thr (c.230T>C) pathogenic?

BCAS4 p.Met77Thr (c.230T>C) is classified Uncertain significance in BCAS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely pathogenic (0.8384); Very rare (popmax 0.00203%, nfe).

How common is BCAS4 p.Met77Thr (c.230T>C) in the general population?

BCAS4 p.Met77Thr (c.230T>C) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about BCAS4 p.Met77Thr (c.230T>C)?

AlphaMissense predicts likely pathogenic (score 0.8384) — an in-silico prediction, not a clinical call.

BCAS4 p.Met77Thr

c.230T>C · VCV3260606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8384	likely pathogenic · top 2% in BCAS4
REVEL	0.252	benign-leaning
SaProt	LLR -10.63	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 4.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 82 kb · p 0.36 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM M107T vs ClinVar M77T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,900 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00174% 28/1,613,696 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,619
European (non-Finnish)grpmax	0.00203%	49,163

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: BCAS4
Protein: p.Met77Thr
Coding: c.230T>C
MANE Select: NM_198799
Type: single nucleotide variant
Location: chr20:50830346 (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-met77thr (accessed [today's date]).

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