Is HADHA p.Val593Met (c.1777G>A) pathogenic?

HADHA p.Val593Met (c.1777G>A) is classified Uncertain significance in HADHA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.2907); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with HADHA p.Val593Met (c.1777G>A)?

HADHA p.Val593Met (c.1777G>A) is associated with Inborn genetic diseases (ClinVar).

How common is HADHA p.Val593Met (c.1777G>A) in the general population?

HADHA p.Val593Met (c.1777G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about HADHA p.Val593Met (c.1777G>A)?

AlphaMissense predicts likely benign (score 0.2907) — an in-silico prediction, not a clinical call.

HADHA p.Val593Met

c.1777G>A · VCV3283416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.2907	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.8	GERP 1.9, phastCons 0.93
Regional constraint	o/e 0.86	unconstrained · MANE · 53 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	21.4	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 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000805% 13/1,613,998 alleles · very rare exomes 5/1,461,794 · genomes 8/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,731
East Asian	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000593%	168,568

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: HADHA
Protein: p.Val593Met
Coding: c.1777G>A
MANE Select: NM_000182
Type: single nucleotide variant
Location: chr2:26193685 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/hadha-p-val593met (accessed [today's date]).

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