Is CLIC1 p.Arg92Ser (c.276G>T) pathogenic?

CLIC1 p.Arg92Ser (c.276G>T) is classified Uncertain significance in CLIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.5285); Ultra-rare (popmax 0.0271%, nfe).

How common is CLIC1 p.Arg92Ser (c.276G>T) in the general population?

CLIC1 p.Arg92Ser (c.276G>T) is ultra-rare (popmax 0.0271%, nfe) (gnomAD).

What do computational predictors say about CLIC1 p.Arg92Ser (c.276G>T)?

AlphaMissense predicts ambiguous (score 0.5285) — an in-silico prediction, not a clinical call.

CLIC1 p.Arg92Ser

c.276G>T · rs149958730 · VCV2351058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0271%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5285	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -7.31	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.65, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 5,455 bp · p 0.00014 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0271% European (non-Finnish) · 320/1,179,914 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.0208% 336/1,612,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0271%	3,687
African / African-American	0.00801%	12,481
Finnishnot grpmax-eligible	0.00794%	12,594
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00167%	60,002

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: CLIC1
Protein: p.Arg92Ser
Coding: c.276G>T
MANE Select: NM_001288
dbSNP: rs149958730
Type: single nucleotide variant
Location: chr6:31733672 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.34 · 18 PDB
Residue 92: a turn

Full CLIC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLIC1 p.Ala157Asp Uncertain significance ★ ⚠ same type
CLIC1 p.Arg204Pro Uncertain significance ★ ⚠ same type
CLIC1 p.Glu234Lys Uncertain significance ★ ⚠ same type
CLIC1 p.Glu4Gly Uncertain significance ★ ⚠ same type
CLIC1 p.Glu9Lys Uncertain significance ★ ⚠ same type
CLIC1 p.Gly196Arg Uncertain significance ★ ⚠ same type
CLIC1 p.Gly61Val Uncertain significance ★ ⚠ same type
CLIC1 p.Gly62Trp 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/clic1-p-arg92ser (accessed [today's date]).

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