Is CLIC6 p.Val555Met (c.1663G>A) pathogenic?

CLIC6 p.Val555Met (c.1663G>A) is classified Uncertain significance in CLIC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-20). AlphaMissense: likely pathogenic (0.8876); Very rare (popmax 0.005%, amr).

How common is CLIC6 p.Val555Met (c.1663G>A) in the general population?

CLIC6 p.Val555Met (c.1663G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CLIC6 p.Val555Met (c.1663G>A)?

AlphaMissense predicts likely pathogenic (score 0.8876) — an in-silico prediction, not a clinical call.

CLIC6 p.Val555Met

c.1663G>A · rs751986325 · VCV2409314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8876	likely pathogenic
REVEL	0.588	indeterminate
SaProt	LLR -13.69	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 5.2	GERP -1.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 46 kb · p 0.04 · regional, not allelic
Overall
CADD	27.2	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 V573M vs ClinVar V555M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,006 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000743% 12/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,002
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,454
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000424%	236,005

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: CLIC6
Protein: p.Val555Met
Coding: c.1663G>A
MANE Select: NM_053277
dbSNP: rs751986325
Type: single nucleotide variant
Location: chr21:34708752 (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-val555met (accessed [today's date]).

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