Is PDHA2 p.Val9Met (c.25G>A) pathogenic?

PDHA2 p.Val9Met (c.25G>A) is classified Uncertain significance in PDHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely benign (0.1674); Ultra-rare (popmax 0.0154%, sas).

How common is PDHA2 p.Val9Met (c.25G>A) in the general population?

PDHA2 p.Val9Met (c.25G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about PDHA2 p.Val9Met (c.25G>A)?

AlphaMissense predicts likely benign (score 0.1674) — an in-silico prediction, not a clinical call.

PDHA2 p.Val9Met

c.25G>A · rs550119402 · VCV3210857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1674	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -0.018
Regional constraint	o/e 1.07	unconstrained · MANE · 1,163 bp · p 0.095 · regional, not allelic
Overall
CADD	11.0	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 0.0154% South Asian · 14/90,964 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00341% 55/1,613,200 alleles · ultra-rare exomes 49/1,460,882 · genomes 6/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,497
European (non-Finnish)	0.00322%	31,042
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,466
Finnishnot grpmax-eligible	0.00156%	63,968

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: PDHA2
Protein: p.Val9Met
Coding: c.25G>A
MANE Select: NM_005390
dbSNP: rs550119402
Type: single nucleotide variant
Location: chr4:95840175 (GRCh38)
Gene constraint: LOEUF 1.406 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 94.08

Full PDHA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDHA2 p.Met227Val Likely pathogenic ★★ same type
PDHA2 p.Ala173Gly Uncertain significance ★ ⚠ same type
PDHA2 p.Ala18Pro Uncertain significance ★ ⚠ same type
PDHA2 p.Ala18Val Uncertain significance ★ ⚠ same type
PDHA2 p.Ala197Val Uncertain significance ★ ⚠ same type
PDHA2 p.Ala32Val Uncertain significance ★ ⚠ same type
PDHA2 p.Ala347Gly Uncertain significance ★ ⚠ same type
PDHA2 p.Ala348Thr 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/pdha2-p-val9met (accessed [today's date]).

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