Is PDHA1 p.Asp348Val (c.1043A>T) pathogenic?

PDHA1 p.Asp348Val (c.1043A>T) is classified Uncertain significance in PDHA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-19). AlphaMissense: likely benign (0.1805); Very rare (popmax 0.000447%, nfe).

How common is PDHA1 p.Asp348Val (c.1043A>T) in the general population?

PDHA1 p.Asp348Val (c.1043A>T) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about PDHA1 p.Asp348Val (c.1043A>T)?

AlphaMissense predicts likely benign (score 0.1805) — an in-silico prediction, not a clinical call.

PDHA1 p.Asp348Val

c.1043A>T · rs1369790452 · VCV2572280

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1805	likely benign
REVEL	0.569	indeterminate
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 711 bp · p 0.5 · regional, not allelic
Overall
CADD	24.4	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 0.000447% European (non-Finnish) · 4/894,354 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.00033% 4/1,210,401 alleles · very rare exomes 4/1,096,886 · genomes 0/113,515 · 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.Asp348Val
Coding: c.1043A>T
MANE Select: NM_000284
dbSNP: rs1369790452
Type: single nucleotide variant
Location: chrX:19359523 (GRCh38)
Structure: AlphaFold pLDDT 94.77 · 9 PDB
Residue 348: an α-helix

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

Similar variants

PDHA1 p.Asp348fs Pathogenic ★ same residue
PDHA1 p.Asp348_Gln351del Uncertain significance ★ 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
PDHA1 p.Ala265= 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-asp348val (accessed [today's date]).

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