Is CLCC1 p.Ser348Arg (c.1044T>G) pathogenic?

CLCC1 p.Ser348Arg (c.1044T>G) is classified Uncertain significance in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-16). AlphaMissense: likely pathogenic (0.9702); Very rare (popmax 0.0055%, nfe).

How common is CLCC1 p.Ser348Arg (c.1044T>G) in the general population?

CLCC1 p.Ser348Arg (c.1044T>G) is very rare (popmax 0.0055%, nfe) (gnomAD).

What do computational predictors say about CLCC1 p.Ser348Arg (c.1044T>G)?

AlphaMissense predicts likely pathogenic (score 0.9702) — an in-silico prediction, not a clinical call.

CLCC1 p.Ser348Arg

c.1044T>G · rs746713662 · VCV1375206

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9702	likely pathogenic · top 1% in CLCC1
REVEL	0.282	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP 0.16, phastCons 0.39
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	23.5	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 0.0055% European (non-Finnish) · 64/1,163,458 alleles

Filtering AF 0.00441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00401%

Overall 0.00448% 64/1,427,176 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.Ser348Arg
Coding: c.1044T>G
MANE Select: NM_001377458
dbSNP: rs746713662
Type: single nucleotide variant
Location: chr1:108937416 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 348: 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.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-ser348arg (accessed [today's date]).

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