Is BCAS3 p.Phe731Ile (c.2191T>A) pathogenic?

BCAS3 p.Phe731Ile (c.2191T>A) is classified Uncertain significance in BCAS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely pathogenic (0.9966); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BCAS3 p.Phe731Ile (c.2191T>A)?

BCAS3 p.Phe731Ile (c.2191T>A) is associated with Inborn genetic diseases (ClinVar).

How common is BCAS3 p.Phe731Ile (c.2191T>A) in the general population?

BCAS3 p.Phe731Ile (c.2191T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BCAS3 p.Phe731Ile (c.2191T>A)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

BCAS3 p.Phe731Ile

c.2191T>A · rs2509389562 · VCV2246576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic · top 4% in BCAS3
REVEL	0.667	pathogenic-leaning
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 689 kb · p 8.1e-12 · regional, not allelic
Overall
CADD	27.1	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 F746I vs ClinVar F731I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.84e-05% 1/1,461,874 alleles · very rare

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: BCAS3
Protein: p.Phe731Ile
Coding: c.2191T>A
MANE Select: NM_017679
dbSNP: rs2509389562
Type: single nucleotide variant
Location: chr17:61078393 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.25
Residue 731: a UniProt-annotated variant site (in hemars)

Full BCAS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BCAS3 p.Ala349Val Uncertain significance ★★ ⚠ same condition
BCAS3 p.Arg254Cys Uncertain significance ★★ ⚠ same condition
BCAS3 p.Asp337Glu Uncertain significance ★★ ⚠ same condition
BCAS3 p.Pro755Leu Uncertain significance ★★ ⚠ same condition
BCAS3 p.Gly159= Likely benign ★★ same condition
BCAS3 c.1638-7789T>C Uncertain significance ★ ⚠ same condition
BCAS3 c.661+6T>C Uncertain significance ★ same condition
BCAS3 p.Ala125Val Uncertain significance ★ ⚠ same condition

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/bcas3-p-phe731ile (accessed [today's date]).

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