Is BMP8A p.Pro74Leu (c.221C>T) pathogenic?

BMP8A p.Pro74Leu (c.221C>T) is classified Uncertain significance in BMP8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.7894); Very rare (popmax 0.000268%, nfe).

How common is BMP8A p.Pro74Leu (c.221C>T) in the general population?

BMP8A p.Pro74Leu (c.221C>T) is very rare (popmax 0.000268%, nfe) (gnomAD).

What do computational predictors say about BMP8A p.Pro74Leu (c.221C>T)?

AlphaMissense predicts likely pathogenic (score 0.7894) — an in-silico prediction, not a clinical call.

BMP8A p.Pro74Leu

c.221C>T · VCV4214337

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000268%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7894	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -6.62	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 4	GERP 0.57, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 102 bp · p 6.9e-07 · regional, not allelic
Overall
CADD	29.8	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 0.000268% European (non-Finnish) · 3/1,118,518 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000205% 3/1,465,502 alleles · very rare exomes 1/1,313,794 · genomes 2/151,708 · joint denominator

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: BMP8A
Protein: p.Pro74Leu
Coding: c.221C>T
MANE Select: NM_181809
Type: single nucleotide variant
Location: chr1:39492212 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.87

Full BMP8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP8A p.Ala144Val Uncertain significance ★★ ⚠ same type
BMP8A p.Arg293His Benign ★★ same type
BMP8A p.Ala102Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala201Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala264Thr Uncertain significance ★ ⚠ same type
BMP8A p.Ala348Val Uncertain significance ★ ⚠ same type
BMP8A p.Ala365Val Uncertain significance ★ same type
BMP8A p.Ala374Thr 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/bmp8a-p-pro74leu (accessed [today's date]).

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