Is BRMS1 p.Ser178Phe (c.533C>T) pathogenic?

BRMS1 p.Ser178Phe (c.533C>T) is classified Uncertain significance in BRMS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-01-03). AlphaMissense: ambiguous (0.4148); Ultra-rare (popmax 0.0584%, amr).

How common is BRMS1 p.Ser178Phe (c.533C>T) in the general population?

BRMS1 p.Ser178Phe (c.533C>T) is ultra-rare (popmax 0.0584%, amr) (gnomAD).

What do computational predictors say about BRMS1 p.Ser178Phe (c.533C>T)?

AlphaMissense predicts ambiguous (score 0.4148) — an in-silico prediction, not a clinical call.

BRMS1 p.Ser178Phe

c.533C>T · rs200297342 · VCV2366990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4148 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0584%, amr)

Computational evidence

Protein change
AlphaMissense	0.4148	ambiguous
REVEL	0.515	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,349 bp · p 0.25 · regional, not allelic
Overall
CADD	32.0	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 0.0584% Admixed American · 35/59,966 alleles

Filtering AF 0.0431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.0109% 175/1,611,232 alleles · ultra-rare exomes 143/1,459,010 · genomes 32/152,222 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.274%	365
Admixed Americangrpmax	0.0584%	1,713
Middle Eastern	0.0381%	2,628
Remaining individualsnot grpmax-eligible	0.0289%	3,464
European (non-Finnish)	0.00314%	31,886
African / African-American	0.00267%	37,444

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: BRMS1
Protein: p.Ser178Phe
Coding: c.533C>T
MANE Select: NM_015399
dbSNP: rs200297342
Type: single nucleotide variant
Location: chr11:66340776 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.23 · 2 PDB

Full BRMS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRMS1 p.Asp175= Benign ★★ same type
BRMS1 c.*105G>C Uncertain significance ★ same type
BRMS1 c.*111C>T Uncertain significance ★ same type
BRMS1 c.*113A>G Uncertain significance ★ same type
BRMS1 c.*122T>A Uncertain significance ★ same type
BRMS1 c.*126G>T Uncertain significance ★ same type
BRMS1 c.*135C>T Uncertain significance ★ same type
BRMS1 c.*167C>A 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/brms1-p-ser178phe (accessed [today's date]).

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