Is PDHA2 p.Arg286Pro (c.857G>C) pathogenic?

PDHA2 p.Arg286Pro (c.857G>C) is classified Benign in PDHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.9838); Low-frequency (popmax 2.9%, mid).

How common is PDHA2 p.Arg286Pro (c.857G>C) in the general population?

PDHA2 p.Arg286Pro (c.857G>C) is low-frequency (popmax 2.9%, mid) (gnomAD).

What do computational predictors say about PDHA2 p.Arg286Pro (c.857G>C)?

AlphaMissense predicts likely pathogenic (score 0.9838) — an in-silico prediction, not a clinical call.

PDHA2 p.Arg286Pro

c.857G>C · rs147966234 · VCV2571210

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9838 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.9%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9838	likely pathogenic · top 5% in PDHA2
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -16.95	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 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,163 bp · p 0.095 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.9% Middle Eastern · 176/6,062 alleles

Filtering AF 2.55% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.42%

Overall 0.866% 13,972/1,614,054 alleles · low-frequency exomes 12,987/1,461,812 · genomes 985/152,242 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.9%	34
Ashkenazi Jewishnot grpmax-eligible	2.88%	35
South Asian	2.17%	46
Remaining individualsnot grpmax-eligible	1.02%	98
European (non-Finnish)	0.83%	121
Admixed American	0.473%	211
Finnishnot grpmax-eligible	0.239%	418
Amishnot grpmax-eligible	0.219%	456
African / African-American	0.136%	735
East Asian	0.00446%	22,439

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.Arg286Pro
Coding: c.857G>C
MANE Select: NM_005390
dbSNP: rs147966234
Type: single nucleotide variant
Location: chr4:95841007 (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.Arg286Cys Uncertain significance ★ ⚠ same residue
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

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-arg286pro (accessed [today's date]).

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