Is BTRC p.Ile181Met (c.543A>G) pathogenic?

BTRC p.Ile181Met (c.543A>G) is classified Uncertain significance in BTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.9385); Very rare (popmax 0.00433%, nfe).

How common is BTRC p.Ile181Met (c.543A>G) in the general population?

BTRC p.Ile181Met (c.543A>G) is very rare (popmax 0.00433%, nfe) (gnomAD).

What do computational predictors say about BTRC p.Ile181Met (c.543A>G)?

AlphaMissense predicts likely pathogenic (score 0.9385) — an in-silico prediction, not a clinical call.

BTRC p.Ile181Met

c.543A>G · rs369777460 · VCV3135591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9385 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00433%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9385	likely pathogenic
REVEL	0.333	indeterminate
SaProt	LLR -12.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -2.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 29 kb · p 5.9e-09 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00433% European (non-Finnish) · 51/1,176,742 alleles

Filtering AF 0.00335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00303%

Overall 0.00335% 54/1,610,384 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00433%	23,073
African / African-American	0.00401%	24,941

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: BTRC
Protein: p.Ile181Met
Coding: c.543A>G
MANE Select: NM_033637
dbSNP: rs369777460
Type: single nucleotide variant
Location: chr10:101521857 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.33 · 15 PDB
Residue 181: an α-helix

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

Similar variants

BTRC p.Leu271Phe Uncertain significance ★★ ⚠ same type
BTRC p.Leu86Phe Uncertain significance ★★ ⚠ same type
BTRC c.556+7C>G Benign ★★ same type
BTRC p.Ala543Ser Benign ★★ same type
BTRC p.Ile229= Benign ★★ same type
BTRC p.Leu387= Likely benign ★★ same type
BTRC p.Pro592Arg Likely benign ★★ same type
BTRC p.Pro592His 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/btrc-p-ile181met (accessed [today's date]).

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