Is BTRC p.Arg549Gln (c.1646G>A) pathogenic?

BTRC p.Arg549Gln (c.1646G>A) is classified Uncertain significance in BTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: ambiguous (0.5059); Ultra-rare (popmax 0.0424%, nfe).

How common is BTRC p.Arg549Gln (c.1646G>A) in the general population?

BTRC p.Arg549Gln (c.1646G>A) is ultra-rare (popmax 0.0424%, nfe) (gnomAD).

What do computational predictors say about BTRC p.Arg549Gln (c.1646G>A)?

AlphaMissense predicts ambiguous (score 0.5059) — an in-silico prediction, not a clinical call.

BTRC p.Arg549Gln

c.1646G>A · rs202032732 · VCV2274501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5059	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -4.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 29 kb · p 5.9e-09 · regional, not allelic
Overall
CADD	29.4	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 0.0424% European (non-Finnish) · 500/1,179,234 alleles

Filtering AF 0.0393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0381%

Overall 0.0339% 547/1,613,250 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0424%	2,358
Remaining individualsnot grpmax-eligible	0.04%	2,500
Admixed American	0.0117%	8,573
South Asian	0.00879%	11,382
African / African-American	0.00667%	15,001
East Asian	0.00446%	22,439

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.Arg549Gln
Coding: c.1646G>A
MANE Select: NM_033637
dbSNP: rs202032732
Type: single nucleotide variant
Location: chr10:101538361 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.33 · 15 PDB
Residue 549: a β-strand

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

Similar variants

BTRC p.Arg549Pro Uncertain significance ★ ⚠ same residue
BTRC p.Arg549= Likely benign ★ same residue
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

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-arg549gln (accessed [today's date]).

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