Is PDHA1 p.Pro110Ala (c.328C>G) pathogenic?

PDHA1 p.Pro110Ala (c.328C>G) is classified Uncertain significance in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-12). AlphaMissense: likely benign (0.0725); Very rare (popmax 0.00591%, eas).

How common is PDHA1 p.Pro110Ala (c.328C>G) in the general population?

PDHA1 p.Pro110Ala (c.328C>G) is very rare (popmax 0.00591%, eas) (gnomAD).

What do computational predictors say about PDHA1 p.Pro110Ala (c.328C>G)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

PDHA1 p.Pro110Ala

c.328C>G · rs2519341189 · VCV3063875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00591%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 5,444 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	24.3	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 0.00591% East Asian · 2/33,823 alleles

Filtering AF 0.000979% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000166% 2/1,206,289 alleles · very rare exomes 2/1,092,673 · genomes 0/113,616 · joint denominator

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: PDHA1
Protein: p.Pro110Ala
Coding: c.328C>G
MANE Select: NM_000284
dbSNP: rs2519341189
Type: single nucleotide variant
Location: chrX:19351317 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB

Full PDHA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDHA1 p.Pro110= Likely benign ★ same residue
PDHA1 p.Pro110His Pathogenic ⚠ same residue
PDHA1 p.Pro110fs Pathogenic same residue
PDHA1 p.Ala169Val Pathogenic ★★★ same type
PDHA1 p.Arg304Ter Pathogenic ★★★ same type
PDHA1 p.Arg378Cys Pathogenic ★★★ ⚠ same type
PDHA1 p.Arg72Cys Likely pathogenic ★★★ same type
PDHA1 p.Ile280Ser 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/pdha1-p-pro110ala (accessed [today's date]).

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