Is CLCC1 p.Trp267Arg (c.799T>C) pathogenic?

CLCC1 p.Trp267Arg (c.799T>C) is classified Uncertain significance in CLCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.8327); Very rare (popmax 0.00224%, eas).

How common is CLCC1 p.Trp267Arg (c.799T>C) in the general population?

CLCC1 p.Trp267Arg (c.799T>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about CLCC1 p.Trp267Arg (c.799T>C)?

AlphaMissense predicts likely pathogenic (score 0.8327) — an in-silico prediction, not a clinical call.

CLCC1 p.Trp267Arg

c.799T>C · VCV3658045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8327	likely pathogenic · top 9% in CLCC1
REVEL	0.574	indeterminate
SaProt	LLR -8.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	24.7	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 0.00224% East Asian · 1/44,618 alleles

Overall 6.99e-05% 1/1,430,140 alleles · very rare

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: CLCC1
Protein: p.Trp267Arg
Coding: c.799T>C
MANE Select: NM_001377458
Type: single nucleotide variant
Location: chr1:108940140 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 267: a UniProt-annotated variant site (found in a patient with sporadic als); a UniProt-annotated variant site (found in a patient with sporadic als; decreases protein stability and expression; decreases protein stability and expression; decreases single channel activity; increases chloride retention in the er while decreasing atp-induced ca(2+) release; in a knockin mouse model causes enhanced er stress and motor neuron degeneration in compound heterozygosity with a hypomorphic allele; leads to embryonic lethality with a ko allele)

Full CLCC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCC1 p.Asp25Glu Pathogenic/Likely pathogenic ★★ same type
CLCC1 p.Ala245Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg208His Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg377Trp Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg381Trp Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg401Gly Uncertain significance ★★ ⚠ same type
CLCC1 p.Arg443Trp 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/clcc1-p-trp267arg (accessed [today's date]).

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