Is BDH2 p.Ala27Val (c.80C>T) pathogenic?

BDH2 p.Ala27Val (c.80C>T) is classified Uncertain significance in BDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.149); Ultra-rare (popmax 0.0267%, amr).

How common is BDH2 p.Ala27Val (c.80C>T) in the general population?

BDH2 p.Ala27Val (c.80C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about BDH2 p.Ala27Val (c.80C>T)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

BDH2 p.Ala27Val

c.80C>T · rs199621816 · VCV2293454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 17 kb · p 0.0025 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0267% Admixed American · 16/59,980 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0119% 192/1,612,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,749
Middle Eastern	0.0165%	6,044
Remaining individualsnot grpmax-eligible	0.016%	6,244
European (non-Finnish)	0.0137%	7,324
African / African-American	0.004%	24,992
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,574

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: BDH2
Protein: p.Ala27Val
Coding: c.80C>T
MANE Select: NM_020139
dbSNP: rs199621816
Type: single nucleotide variant
Location: chr4:103095274 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 1 PDB
Residue 27: an α-helix

Full BDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BDH2 p.Thr182= Benign ★★ same type
BDH2 p.Ala14Thr Uncertain significance ★ ⚠ same type
BDH2 p.Ala23Pro Uncertain significance ★ ⚠ same type
BDH2 p.Arg199Trp Uncertain significance ★ ⚠ same type
BDH2 p.Arg3Gln Uncertain significance ★ ⚠ same type
BDH2 p.Arg55Cys Uncertain significance ★ ⚠ same type
BDH2 p.Arg55His Uncertain significance ★ ⚠ same type
BDH2 p.Asn103His 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/bdh2-p-ala27val (accessed [today's date]).

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