Is BDH2 p.Ala23Pro (c.67G>C) pathogenic?

BDH2 p.Ala23Pro (c.67G>C) is classified Uncertain significance in BDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). AlphaMissense: likely pathogenic (0.9567); Ultra-rare (popmax 0.0246%, nfe).

How common is BDH2 p.Ala23Pro (c.67G>C) in the general population?

BDH2 p.Ala23Pro (c.67G>C) is ultra-rare (popmax 0.0246%, nfe) (gnomAD).

What do computational predictors say about BDH2 p.Ala23Pro (c.67G>C)?

AlphaMissense predicts likely pathogenic (score 0.9567) — an in-silico prediction, not a clinical call.

BDH2 p.Ala23Pro

c.67G>C · rs147784208 · VCV2459719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9567 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9567	likely pathogenic
REVEL	0.74	pathogenic-leaning
SaProt	LLR -15.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.87, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 17 kb · p 0.0025 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0246% European (non-Finnish) · 290/1,178,126 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.022% 354/1,611,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
European (non-Finnish)grpmax	0.0246%	4,062
Remaining individualsnot grpmax-eligible	0.0144%	6,934
African / African-American	0.004%	25,018

Ashkenazi Jewish 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: BDH2
Protein: p.Ala23Pro
Coding: c.67G>C
MANE Select: NM_020139
dbSNP: rs147784208
Type: single nucleotide variant
Location: chr4:103096188 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 1 PDB
Residue 23: 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.Ala27Val 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-ala23pro (accessed [today's date]).

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