Is CLHC1 p.Glu399Ala (c.1196A>C) pathogenic?

CLHC1 p.Glu399Ala (c.1196A>C) is classified Uncertain significance in CLHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.2045); Absent from gnomAD v4.1.

How common is CLHC1 p.Glu399Ala (c.1196A>C) in the general population?

CLHC1 p.Glu399Ala (c.1196A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLHC1 p.Glu399Ala (c.1196A>C)?

AlphaMissense predicts likely benign (score 0.2045) — an in-silico prediction, not a clinical call.

CLHC1 p.Glu399Ala

c.1196A>C · VCV4003626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2045 · 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	0.2045	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 47 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	25.7	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: CLHC1
Protein: p.Glu399Ala
Coding: c.1196A>C
MANE Select: NM_152385
Type: single nucleotide variant
Location: chr2:55180698 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.85

Full CLHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLHC1 p.Ala121Thr Uncertain significance ★ ⚠ same type
CLHC1 p.Ala196Val Uncertain significance ★ ⚠ same type
CLHC1 p.Ala336Gly Uncertain significance ★ ⚠ same type
CLHC1 p.Ala367Val Uncertain significance ★ ⚠ same type
CLHC1 p.Ala567Thr Uncertain significance ★ ⚠ same type
CLHC1 p.Arg206Gly Uncertain significance ★ ⚠ same type
CLHC1 p.Arg286Cys Uncertain significance ★ ⚠ same type
CLHC1 p.Arg286Pro 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/clhc1-p-glu399ala (accessed [today's date]).

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