Is CLCC1 p.Arg208Cys (c.622C>T) pathogenic?

CLCC1 p.Arg208Cys (c.622C>T) is classified Uncertain significance in CLCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely benign (0.1417); Very rare (popmax 0.00195%, nfe).

How common is CLCC1 p.Arg208Cys (c.622C>T) in the general population?

CLCC1 p.Arg208Cys (c.622C>T) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about CLCC1 p.Arg208Cys (c.622C>T)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

CLCC1 p.Arg208Cys

c.622C>T · rs371801332 · VCV2339326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	donor loss, 4 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 16 kb · p 3.3e-06 · regional, not allelic
Overall
CADD	23.9	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 0.00195% European (non-Finnish) · 23/1,179,812 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,613,742 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,296
African / African-American	0.00134%	74,888

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.Arg208Cys
Coding: c.622C>T
MANE Select: NM_001377458
dbSNP: rs371801332
Type: single nucleotide variant
Location: chr1:108943555 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.13

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

Similar variants

CLCC1 p.Arg208His 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.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-arg208cys (accessed [today's date]).

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