Is EHHADH p.Ile456Val (c.1366A>G) pathogenic?

EHHADH p.Ile456Val (c.1366A>G) is classified Uncertain significance in EHHADH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.083); Very rare (popmax 0.0011%, sas).

How common is EHHADH p.Ile456Val (c.1366A>G) in the general population?

EHHADH p.Ile456Val (c.1366A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about EHHADH p.Ile456Val (c.1366A>G)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

EHHADH p.Ile456Val

c.1366A>G · VCV4247569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.96	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 1.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.44 · regional, not allelic
Overall
CADD	14.13	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000169%	590,016

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: EHHADH
Protein: p.Ile456Val
Coding: c.1366A>G
MANE Select: NM_001966
Type: single nucleotide variant
Location: chr3:185193032 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.07
Residue 456: the '3-hydroxyacyl-coa dehydrogenase' region

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

Similar variants

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EHHADH p.Ala118Val Uncertain significance ★★ ⚠ same type
EHHADH p.Ala294Val Uncertain significance ★★ ⚠ same type
EHHADH p.Arg183Gly Uncertain significance ★★ ⚠ same type
EHHADH p.Arg633Cys Uncertain significance ★★ ⚠ same type
EHHADH p.Arg64Cys Uncertain significance ★★ ⚠ same type
EHHADH p.Asn629Ser Uncertain significance ★★ ⚠ same type
EHHADH p.Asp42Glu 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/ehhadh-p-ile456val (accessed [today's date]).

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