Is BMP1 p.Ala538Val (c.1613C>T) pathogenic?

BMP1 p.Ala538Val (c.1613C>T) is classified Uncertain significance in BMP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.5972); Very rare (popmax 0.00511%, amr).

How common is BMP1 p.Ala538Val (c.1613C>T) in the general population?

BMP1 p.Ala538Val (c.1613C>T) is very rare (popmax 0.00511%, amr) (gnomAD).

What do computational predictors say about BMP1 p.Ala538Val (c.1613C>T)?

AlphaMissense predicts likely pathogenic (score 0.5972) — an in-silico prediction, not a clinical call.

BMP1 p.Ala538Val

c.1613C>T · VCV4536101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00511%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5972	likely pathogenic
REVEL	0.309	indeterminate
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.50	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 35 kb · p 1e-07 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00511% Admixed American · 3/58,738 alleles

Filtering AF 0.00136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000676%

Overall 0.000497% 8/1,609,926 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00511%	19,579
Remaining individualsnot grpmax-eligible	0.00161%	62,296
European (non-Finnish)	0.000339%	294,680

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: BMP1
Protein: p.Ala538Val
Coding: c.1613C>T
MANE Select: NM_006129
Type: single nucleotide variant
Location: chr8:22194893 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.89 · 8 PDB
Residue 538: the cub 2 domain

Full BMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP1 p.Ala538= Likely benign ★ same residue
BMP1 p.Cys183Ter Pathogenic/Likely pathogenic ★★ same type
BMP1 p.Gln70Ter Pathogenic/Likely pathogenic ★★ same type
BMP1 c.1443+6T>C Uncertain significance ★★ same type
BMP1 c.1639+4C>G Uncertain significance ★★ same type
BMP1 c.2233+4C>T Uncertain significance ★★ same type
BMP1 c.*452A>C Uncertain significance ★★ same type
BMP1 p.Ala657Thr 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/bmp1-p-ala538val (accessed [today's date]).

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