Is PDHA1 p.Asp187His (c.559G>C) pathogenic?

PDHA1 p.Asp187His (c.559G>C) is classified Uncertain significance in PDHA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-29). AlphaMissense: likely benign (0.2213); Absent from gnomAD v4.1.

How common is PDHA1 p.Asp187His (c.559G>C) in the general population?

PDHA1 p.Asp187His (c.559G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDHA1 p.Asp187His (c.559G>C)?

AlphaMissense predicts likely benign (score 0.2213) — an in-silico prediction, not a clinical call.

PDHA1 p.Asp187His

c.559G>C · rs2147179768 · VCV1307558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2213 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2213	likely benign
REVEL	0.641	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.8	GERP 2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 5,444 bp · p 1.2e-20 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDHA1
Protein: p.Asp187His
Coding: c.559G>C
MANE Select: NM_000284
dbSNP: rs2147179768
Type: single nucleotide variant
Location: chrX:19354539 (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.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
PDHA1 p.Ala265= Benign ★★★ same type
PDHA1 p.Glu333Asp Benign ★★★ same type
PDHA1 p.Met282Leu Benign ★★★ 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-asp187his (accessed [today's date]).

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