Is CLCC1 p.Ala450Thr (c.1348G>A) pathogenic?

CLCC1 p.Ala450Thr (c.1348G>A) is classified Uncertain significance in CLCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.0687); Very rare (popmax 0.00272%, nfe).

How common is CLCC1 p.Ala450Thr (c.1348G>A) in the general population?

CLCC1 p.Ala450Thr (c.1348G>A) is very rare (popmax 0.00272%, nfe) (gnomAD).

What do computational predictors say about CLCC1 p.Ala450Thr (c.1348G>A)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

CLCC1 p.Ala450Thr

c.1348G>A · rs755037232 · VCV2268062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.01	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 -0.52	GERP -0.19
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% European (non-Finnish) · 31/1,138,008 alleles

Filtering AF 0.00195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0017%

Overall 0.00217% 33/1,524,126 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00272%	36,710
Admixed American	0.00219%	45,642
Remaining individualsnot grpmax-eligible	0.00171%	58,604

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.Ala450Thr
Coding: c.1348G>A
MANE Select: NM_001377458
dbSNP: rs755037232
Type: single nucleotide variant
Location: chr1:108937112 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 450: the 'disordered' region; 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

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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-ala450thr (accessed [today's date]).

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