Is BTRC p.Arg419Gln (c.1256G>A) pathogenic?

BTRC p.Arg419Gln (c.1256G>A) is classified Uncertain significance in BTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely pathogenic (0.6298); Very rare (popmax 0.004%, afr).

How common is BTRC p.Arg419Gln (c.1256G>A) in the general population?

BTRC p.Arg419Gln (c.1256G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about BTRC p.Arg419Gln (c.1256G>A)?

AlphaMissense predicts likely pathogenic (score 0.6298) — an in-silico prediction, not a clinical call.

BTRC p.Arg419Gln

c.1256G>A · rs376316565 · VCV3135585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6298	likely pathogenic
REVEL	0.345	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 29 kb · p 5.9e-09 · regional, not allelic
Overall
CADD	34.0	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 0.004% African / African-American · 3/75,030 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00161% 26/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,010
European (non-Finnish)	0.00169%	59,001
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,512
South Asian	0.0011%	91,080

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.Arg419Gln
Coding: c.1256G>A
MANE Select: NM_033637
dbSNP: rs376316565
Type: single nucleotide variant
Location: chr10:101534819 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.33 · 15 PDB
Residue 419: a β-strand

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-arg419gln (accessed [today's date]).

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