Is BTBD2 p.Val115Met (c.343G>A) pathogenic?

BTBD2 p.Val115Met (c.343G>A) is classified Uncertain significance in BTBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: ambiguous (0.4538); Very rare (popmax 0.00332%, nfe).

How common is BTBD2 p.Val115Met (c.343G>A) in the general population?

BTBD2 p.Val115Met (c.343G>A) is very rare (popmax 0.00332%, nfe) (gnomAD).

What do computational predictors say about BTBD2 p.Val115Met (c.343G>A)?

AlphaMissense predicts ambiguous (score 0.4538) — an in-silico prediction, not a clinical call.

BTBD2 p.Val115Met

c.343G>A · rs1223450066 · VCV2511311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00332%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4538	ambiguous
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.60	donor loss · deltas
Constraint at this position
Conservation	phyloP 0.19	GERP -2.1, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.86 · regional, not allelic
Overall
CADD	25.7	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 0.00332% European (non-Finnish) · 39/1,173,122 alleles

Filtering AF 0.00249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.00265% 42/1,585,270 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00332%	30,080
Remaining individualsnot grpmax-eligible	0.00324%	30,878
African / African-American	0.00136%	73,538

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: BTBD2
Protein: p.Val115Met
Coding: c.343G>A
MANE Select: NM_017797
dbSNP: rs1223450066
Type: single nucleotide variant
Location: chr19:2015361 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 1 PDB

Full BTBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD2 p.Ala201Ser Uncertain significance ★ ⚠ same type
BTBD2 p.Ala201Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala33Gly Uncertain significance ★ ⚠ same type
BTBD2 p.Ala37Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala3Thr Uncertain significance ★ ⚠ same type
BTBD2 p.Ala41Glu Uncertain significance ★ ⚠ same type
BTBD2 p.Ala42Ser Uncertain significance ★ ⚠ same type
BTBD2 p.Ala446Val 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/btbd2-p-val115met (accessed [today's date]).

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