Is BMS1 p.Pro742Leu (c.2225C>T) pathogenic?

BMS1 p.Pro742Leu (c.2225C>T) is classified Uncertain significance in BMS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.0969); Very rare (popmax 0.00223%, eas); Associated with aplasia cutis congenita.

What condition is associated with BMS1 p.Pro742Leu (c.2225C>T)?

BMS1 p.Pro742Leu (c.2225C>T) is associated with aplasia cutis congenita (ClinVar).

How common is BMS1 p.Pro742Leu (c.2225C>T) in the general population?

BMS1 p.Pro742Leu (c.2225C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BMS1 p.Pro742Leu (c.2225C>T)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

BMS1 p.Pro742Leu

c.2225C>T · rs1286643427 · VCV1275745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aplasia cutis congenita

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.55	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 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 26 kb · p 0.68 · regional, not allelic
Overall
CADD	19.42	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,900 alleles

Overall 0.00197% 3/152,168 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,900
Admixed American	0.00167%	60,008
African / African-American	0.00134%	74,894

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: BMS1
Protein: p.Pro742Leu
Coding: c.2225C>T
MANE Select: NM_014753
dbSNP: rs1286643427
Type: single nucleotide variant
Location: chr10:42798603 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 72.04 · 3 PDB

Full BMS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

aplasia cutis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BMS1 p.Leu732Val Uncertain significance ★ ⚠ same condition
BMS1 p.Arg930His Pathogenic same condition
BMS1 p.Ser295fs Uncertain significance ★ same condition
BMS1 p.Ala214Val Benign/Likely benign ★★ same type
BMS1 p.Ala500= Benign/Likely benign ★★ same type
BMS1 p.Arg237His Benign ★★ same type
BMS1 p.Arg38Trp Benign/Likely benign ★★ ⚠ same type
BMS1 p.Arg863= Benign ★★ 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/bms1-p-pro742leu (accessed [today's date]).

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