Is PDHA2 p.Phe5Ser (c.14T>C) pathogenic?

PDHA2 p.Phe5Ser (c.14T>C) is classified Uncertain significance in PDHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.0786); Ultra-rare (popmax 0.0174%, afr).

How common is PDHA2 p.Phe5Ser (c.14T>C) in the general population?

PDHA2 p.Phe5Ser (c.14T>C) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about PDHA2 p.Phe5Ser (c.14T>C)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

PDHA2 p.Phe5Ser

c.14T>C · VCV3887394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -3.00	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 -0.006	GERP -3.2
Regional constraint	o/e 1.07	unconstrained · MANE · 1,163 bp · p 0.095 · regional, not allelic
Overall
CADD	5.014	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 0.0174% African / African-American · 13/74,914 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000869% 14/1,610,728 alleles · ultra-rare exomes 7/1,458,548 · genomes 7/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,763
Admixed American	0.00167%	59,876

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.Phe5Ser
Coding: c.14T>C
MANE Select: NM_005390
Type: single nucleotide variant
Location: chr4:95840164 (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-phe5ser (accessed [today's date]).

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