Is CLCC1 p.Ser368Arg (c.1104C>A) pathogenic?

CLCC1 p.Ser368Arg (c.1104C>A) is classified Benign in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0563); Common (popmax 57.2%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CLCC1 p.Ser368Arg (c.1104C>A)?

AlphaMissense predicts likely benign (score 0.0563) — an in-silico prediction, not a clinical call.

CLCC1 p.Ser368Arg

Q: How common is CLCC1 p.Ser368Arg (c.1104C>A) in the general population?

CLCC1 p.Ser368Arg (c.1104C>A) is common (popmax 57.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1104C>A · rs168107 · VCV1166558

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0563 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0563	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.22	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 0.66	GERP -2.4, phastCons 0.93
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	1.333	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 57.2% African / African-American · 42,852/74,940 alleles

Filtering AF 56.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.5%

Overall 27.5% 442,933/1,613,536 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	57.2%	2
Ashkenazi Jewishnot grpmax-eligible	36.8%	3
Middle Eastern	32.5%	3
Finnishnot grpmax-eligible	28.5%	4
Amishnot grpmax-eligible	28.4%	4
Remaining individualsnot grpmax-eligible	27.8%	4
European (non-Finnish)	26.5%	4
South Asian	25.9%	4
Admixed American	23.1%	4
East Asian	3.84%	26

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.Ser368Arg
Coding: c.1104C>A
MANE Select: NM_001377458
dbSNP: rs168107
Type: single nucleotide variant
Location: chr1:108937356 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 368: a UniProt-annotated variant site (found in a patient with sporadic als); a UniProt-annotated variant site (in); the 'disordered' region

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

Similar variants

CLCC1 p.Ser368Gly Uncertain significance ★ ⚠ 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-ser368arg (accessed [today's date]).

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