Is CLIC6 p.Asp499His (c.1495G>C) pathogenic?

CLIC6 p.Asp499His (c.1495G>C) is classified Uncertain significance in CLIC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.941); Absent from gnomAD v4.1.

How common is CLIC6 p.Asp499His (c.1495G>C) in the general population?

CLIC6 p.Asp499His (c.1495G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLIC6 p.Asp499His (c.1495G>C)?

AlphaMissense predicts likely pathogenic (score 0.941) — an in-silico prediction, not a clinical call.

CLIC6 p.Asp499His

c.1495G>C · VCV4003660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.941	likely pathogenic
REVEL	0.385	indeterminate
SaProt	LLR -13.33	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 46 kb · p 0.04 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D517H vs ClinVar D499H) — verify the residue.

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: CLIC6
Protein: p.Asp499His
Coding: c.1495G>C
MANE Select: NM_053277
Type: single nucleotide variant
Location: chr21:34707954 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.24

Full CLIC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC6 p.Arg436Pro Benign ★★ same type
CLIC6 p.Arg640Lys Benign ★★ same type
CLIC6 p.Asp616= Benign ★★ same type
CLIC6 p.Glu401= Likely benign ★★ same type
CLIC6 p.Ile651Val Benign ★★ same type
CLIC6 p.Ser550= Benign ★★ same type
CLIC6 p.Thr667= Benign ★★ same type
CLIC6 p.Val180Leu 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/clic6-p-asp499his (accessed [today's date]).

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