Is BCAS1 p.Pro528Leu (c.1583C>T) pathogenic?

BCAS1 p.Pro528Leu (c.1583C>T) is classified Uncertain significance in BCAS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.0716); Ultra-rare (popmax 0.0198%, sas).

How common is BCAS1 p.Pro528Leu (c.1583C>T) in the general population?

BCAS1 p.Pro528Leu (c.1583C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about BCAS1 p.Pro528Leu (c.1583C>T)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

BCAS1 p.Pro528Leu

c.1583C>T · rs145068978 · VCV2399393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -6.65	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 2.1	GERP -0.099, phastCons 0.99
Regional constraint	o/e 1.03	unconstrained · MANE · 114 kb · p 0.43 · regional, not allelic
Overall
CADD	18.25	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 P483L vs ClinVar P528L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0198% South Asian · 18/91,054 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00502% 81/1,613,742 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,059
African / African-American	0.0174%	5,759
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0096%	10,417
European (non-Finnish)	0.00356%	28,094
Admixed American	0.00167%	59,980

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: BCAS1
Protein: p.Pro528Leu
Coding: c.1583C>T
MANE Select: NM_001366298
dbSNP: rs145068978
Type: single nucleotide variant
Location: chr20:53953664 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.00
Residue 528: the 'disordered' region

Full BCAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCAS1 c.1486-10G>A Benign ★★ same type
BCAS1 p.Ala180= Benign ★★ same type
BCAS1 p.Ser519= Benign ★★ same type
BCAS1 p.Thr171Met Benign ★★ ⚠ same type
BCAS1 p.Thr56Met Benign ★★ ⚠ same type
BCAS1 p.Thr578= Benign ★★ same type
BCAS1 p.Thr67Met Benign/Likely benign ★★ ⚠ same type
BCAS1 p.Ala184Val 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/bcas1-p-pro528leu (accessed [today's date]).

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