Is CLCN6 p.Arg640Ser (c.1918C>A) pathogenic?

CLCN6 p.Arg640Ser (c.1918C>A) is classified Uncertain significance in CLCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-30). AlphaMissense: ambiguous (0.5546); Very rare (popmax 0.00134%, afr).

How common is CLCN6 p.Arg640Ser (c.1918C>A) in the general population?

CLCN6 p.Arg640Ser (c.1918C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CLCN6 p.Arg640Ser (c.1918C>A)?

AlphaMissense predicts ambiguous (score 0.5546) — an in-silico prediction, not a clinical call.

CLCN6 p.Arg640Ser

c.1918C>A · rs770239210 · VCV1954078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5546 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.5546	ambiguous
REVEL	0.434	indeterminate
SaProt	LLR -5.78	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.63, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 34 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	21.9	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 0.00134% African / African-American · 1/74,862 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,734 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,862
European (non-Finnish)	0.000424%	235,987

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: CLCN6
Protein: p.Arg640Ser
Coding: c.1918C>A
MANE Select: NM_001286
dbSNP: rs770239210
Type: single nucleotide variant
Location: chr1:11836091 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 3 PDB
Residue 640: the cbs 1 domain

Full CLCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN6 p.Arg640Cys Uncertain significance ★★ ⚠ same residue
CLCN6 p.Arg640His Uncertain significance ★ ⚠ same residue
CLCN6 p.Arg640= Likely benign ★ same residue
CLCN6 p.Tyr553Cys Pathogenic ★★ ⚠ same type
CLCN6 p.Ala127Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala144Glu Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala256Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala392Val 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/clcn6-p-arg640ser (accessed [today's date]).

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