Is BTRC p.Ile439Val (c.1315A>G) pathogenic?

BTRC p.Ile439Val (c.1315A>G) is classified Uncertain significance in BTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: ambiguous (0.3735); Ultra-rare (popmax 0.0336%, nfe).

How common is BTRC p.Ile439Val (c.1315A>G) in the general population?

BTRC p.Ile439Val (c.1315A>G) is ultra-rare (popmax 0.0336%, nfe) (gnomAD).

What do computational predictors say about BTRC p.Ile439Val (c.1315A>G)?

AlphaMissense predicts ambiguous (score 0.3735) — an in-silico prediction, not a clinical call.

BTRC p.Ile439Val

c.1315A>G · rs200146282 · VCV2045020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3735	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -10.66	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.64	donor gain · deltas
Pangolin	Δ0.44	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 29 kb · p 5.9e-09 · regional, not allelic
Overall
CADD	29.9	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 0.0336% European (non-Finnish) · 397/1,180,016 alleles

Filtering AF 0.0309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0298%

Overall 0.0281% 453/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.05%	2,001
European (non-Finnish)grpmax	0.0336%	2,972
Remaining individualsnot grpmax-eligible	0.0288%	3,472
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asian	0.00329%	30,361
African / African-American	0.00267%	37,450

Finnish 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: BTRC
Protein: p.Ile439Val
Coding: c.1315A>G
MANE Select: NM_033637
dbSNP: rs200146282
Type: single nucleotide variant
Location: chr10:101534878 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.33 · 15 PDB
Residue 439: 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-ile439val (accessed [today's date]).

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