Is CLCC1 p.Ser438Arg (c.1314C>A) pathogenic?

CLCC1 p.Ser438Arg (c.1314C>A) is classified Uncertain significance in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4218); Very rare (popmax 0.00699%, nfe).

How common is CLCC1 p.Ser438Arg (c.1314C>A) in the general population?

CLCC1 p.Ser438Arg (c.1314C>A) is very rare (popmax 0.00699%, nfe) (gnomAD).

What do computational predictors say about CLCC1 p.Ser438Arg (c.1314C>A)?

AlphaMissense predicts ambiguous (score 0.4218) — an in-silico prediction, not a clinical call.

CLCC1 p.Ser438Arg

c.1314C>A · rs145516760 · VCV860365

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00699%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4218	ambiguous
REVEL	0.196	benign-leaning
SaProt	LLR -6.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	24.8	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 0.00699% European (non-Finnish) · 81/1,158,294 alleles

Filtering AF 0.00573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00524%

Overall 0.00555% 87/1,568,002 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00699%	14,300
African / African-American	0.00409%	24,467
Remaining individualsnot grpmax-eligible	0.0033%	30,316
Admixed American	0.00186%	53,788

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.Ser438Arg
Coding: c.1314C>A
MANE Select: NM_001377458
dbSNP: rs145516760
Type: single nucleotide variant
Location: chr1:108937146 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 438: a modified residue (phosphoserine); 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.Ser438Ile 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-ser438arg (accessed [today's date]).

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