Is PDHA2 p.Pro248Ser (c.742C>T) pathogenic?

PDHA2 p.Pro248Ser (c.742C>T) is classified Uncertain significance in PDHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: ambiguous (0.464); Very rare (popmax 0.00834%, amr).

How common is PDHA2 p.Pro248Ser (c.742C>T) in the general population?

PDHA2 p.Pro248Ser (c.742C>T) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about PDHA2 p.Pro248Ser (c.742C>T)?

AlphaMissense predicts ambiguous (score 0.464) — an in-silico prediction, not a clinical call.

PDHA2 p.Pro248Ser

c.742C>T · rs200847664 · VCV2487131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.464	ambiguous
REVEL	0.852	moderately pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,163 bp · p 0.095 · regional, not allelic
Overall
CADD	21.6	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 0.00834% Admixed American · 5/59,986 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00558% 90/1,613,922 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Admixed Americangrpmax	0.00834%	11,997
European (non-Finnish)	0.005%	20,000
African / African-American	0.00134%	74,870

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: PDHA2
Protein: p.Pro248Ser
Coding: c.742C>T
MANE Select: NM_005390
dbSNP: rs200847664
Type: single nucleotide variant
Location: chr4:95840892 (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-pro248ser (accessed [today's date]).

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