Is CLCC1 p.Ala332Val (c.995C>T) pathogenic?

CLCC1 p.Ala332Val (c.995C>T) is classified Benign in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0703); Common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CLCC1 p.Ala332Val (c.995C>T)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

CLCC1 p.Ala332Val

Q: How common is CLCC1 p.Ala332Val (c.995C>T) in the general population?

CLCC1 p.Ala332Val (c.995C>T) is common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.995C>T · rs36032236 · VCV1168662

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -2.9
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	2.396	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 7.14% Middle Eastern · 433/6,062 alleles

Filtering AF 6.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.37%

Overall 2.04% 32,934/1,614,018 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	7.14%	14
Ashkenazi Jewishnot grpmax-eligible	5.04%	20
South Asian	2.41%	41
Remaining individualsnot grpmax-eligible	2.37%	42
European (non-Finnish)	2.19%	46
Admixed American	1.48%	68
African / African-American	0.385%	260
Finnishnot grpmax-eligible	0.281%	356
East Asian	0.265%	377
Amishnot grpmax-eligible	0.11%	912

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.Ala332Val
Coding: c.995C>T
MANE Select: NM_001377458
dbSNP: rs36032236
Type: single nucleotide variant
Location: chr1:108939682 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 332: a UniProt-annotated variant site (found in a patient with sporadic als)

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

Similar variants

CLCC1 p.Ala332= Benign ★ same residue
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

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-ala332val (accessed [today's date]).

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