Is CLCC1 p.Arg443Trp (c.1327C>T) pathogenic?

CLCC1 p.Arg443Trp (c.1327C>T) is classified Uncertain significance in CLCC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1122); Ultra-rare (popmax 0.055%, sas).

How common is CLCC1 p.Arg443Trp (c.1327C>T) in the general population?

CLCC1 p.Arg443Trp (c.1327C>T) is ultra-rare (popmax 0.055%, sas) (gnomAD).

What do computational predictors say about CLCC1 p.Arg443Trp (c.1327C>T)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

CLCC1 p.Arg443Trp

c.1327C>T · rs778267768 · VCV843901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -9.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	33.0	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 0.055% South Asian · 43/78,158 alleles

Filtering AF 0.0419% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0373%

Overall 0.0103% 158/1,541,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.055%	1,818
Admixed American	0.0388%	2,580
East Asian	0.0205%	4,880
Remaining individualsnot grpmax-eligible	0.0135%	7,416
European (non-Finnish)	0.00646%	15,483
Finnishnot grpmax-eligible	0.00489%	20,437
African / African-American	0.00276%	36,209

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.Arg443Trp
Coding: c.1327C>T
MANE Select: NM_001377458
dbSNP: rs778267768
Type: single nucleotide variant
Location: chr1:108937133 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13
Residue 443: 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.Arg443Gln 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-arg443trp (accessed [today's date]).

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