Is PDHA2 p.Ile6Phe (c.16A>T) pathogenic?

PDHA2 p.Ile6Phe (c.16A>T) is classified Uncertain significance in PDHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0245%, eas).

How common is PDHA2 p.Ile6Phe (c.16A>T) in the general population?

PDHA2 p.Ile6Phe (c.16A>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about PDHA2 p.Ile6Phe (c.16A>T)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

PDHA2 p.Ile6Phe

c.16A>T · rs199746220 · VCV2525751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -5.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP -0.96
Regional constraint	o/e 1.07	unconstrained · MANE · 1,163 bp · p 0.095 · regional, not allelic
Overall
CADD	8.613	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 0.0245% East Asian · 11/44,856 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000807% 13/1,611,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,078
Remaining individualsnot grpmax-eligible	0.0016%	62,368
European (non-Finnish)	8.48e-05%	1,178,732

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.Ile6Phe
Coding: c.16A>T
MANE Select: NM_005390
dbSNP: rs199746220
Type: single nucleotide variant
Location: chr4:95840166 (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-ile6phe (accessed [today's date]).

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