Is BDH2 p.Ile128Ser (c.383T>G) pathogenic?

BDH2 p.Ile128Ser (c.383T>G) is classified Uncertain significance in BDH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.9782); Very rare (popmax 0.000509%, nfe).

How common is BDH2 p.Ile128Ser (c.383T>G) in the general population?

BDH2 p.Ile128Ser (c.383T>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about BDH2 p.Ile128Ser (c.383T>G)?

AlphaMissense predicts likely pathogenic (score 0.9782) — an in-silico prediction, not a clinical call.

BDH2 p.Ile128Ser

c.383T>G · VCV4203896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9782	likely pathogenic · top 6% in BDH2
REVEL	0.761	pathogenic-leaning
SaProt	LLR -17.83	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 17 kb · p 0.0025 · regional, not allelic
Overall
CADD	32.0	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 0.000509% European (non-Finnish) · 6/1,179,290 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,611,760 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,197
European (non-Finnish)grpmax	0.000509%	196,548

Remaining individuals 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.Ile128Ser
Coding: c.383T>G
MANE Select: NM_020139
Type: single nucleotide variant
Location: chr4:103086515 (GRCh38)
Gene constraint: LOEUF 1.253 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.46 · 1 PDB
Residue 128: a β-strand

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.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

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-ile128ser (accessed [today's date]).

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