Is BMP5 p.Ser435Thr (c.1304G>C) pathogenic?

BMP5 p.Ser435Thr (c.1304G>C) is classified Uncertain significance in BMP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: ambiguous (0.3476); Very rare (popmax 0.00167%, amr).

How common is BMP5 p.Ser435Thr (c.1304G>C) in the general population?

BMP5 p.Ser435Thr (c.1304G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BMP5 p.Ser435Thr (c.1304G>C)?

AlphaMissense predicts ambiguous (score 0.3476) — an in-silico prediction, not a clinical call.

BMP5 p.Ser435Thr

c.1304G>C · rs768786761 · VCV2554474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.3476	ambiguous
REVEL	0.549	indeterminate
SaProt	LLR -4.86	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 119 kb · p 0.39 · regional, not allelic
Overall
CADD	25.5	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 0.00167% Admixed American · 1/59,780 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00118% 19/1,611,680 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0373%	2,684
Remaining individualsnot grpmax-eligible	0.00641%	15,595
Admixed Americangrpmax	0.00167%	59,780
European (non-Finnish)	0.000255%	392,808

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BMP5
Protein: p.Ser435Thr
Coding: c.1304G>C
MANE Select: NM_021073
dbSNP: rs768786761
Type: single nucleotide variant
Location: chr6:55755594 (GRCh38)
Gene constraint: LOEUF 0.711 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.85
Residue 435: a disulfide bond

Full BMP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMP5 p.Ala103Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala118Asp Uncertain significance ★ ⚠ same type
BMP5 p.Ala25Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala307Glu Uncertain significance ★ ⚠ same type
BMP5 p.Ala317Val Uncertain significance ★ ⚠ same type
BMP5 p.Ala74Thr Uncertain significance ★ ⚠ same type
BMP5 p.Ala77Val Uncertain significance ★ ⚠ same type
BMP5 p.Arg125Cys 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/bmp5-p-ser435thr (accessed [today's date]).

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