Is CLCN7 p.Ser9Pro (c.25T>C) pathogenic?

CLCN7 p.Ser9Pro (c.25T>C) is classified Uncertain significance in CLCN7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.6936); Absent from gnomAD v4.1.

How common is CLCN7 p.Ser9Pro (c.25T>C) in the general population?

CLCN7 p.Ser9Pro (c.25T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN7 p.Ser9Pro (c.25T>C)?

AlphaMissense predicts likely pathogenic (score 0.6936) — an in-silico prediction, not a clinical call.

CLCN7 p.Ser9Pro

c.25T>C · VCV3687102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6936 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,492,234)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6936	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 13 kb · p 0.031 · regional, not allelic
Overall
CADD	29.7	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

No allele count reported in gnomAD v4.1 (AN 1,492,234). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CLCN7
Protein: p.Ser9Pro
Coding: c.25T>C
MANE Select: NM_001287
Type: single nucleotide variant
Location: chr16:1474950 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 9: the 'disordered' region; a modified residue (phosphoserine)

Full CLCN7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN7 p.Ser9Cys Uncertain significance ★ same residue
CLCN7 p.Ser9= Likely benign ★ same residue
CLCN7 c.1448-2A>G Likely pathogenic ★★ same type
CLCN7 c.1617+119G>A Pathogenic ★★ same type
CLCN7 c.739-18G>A Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Gln Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Trp Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg526Gln Likely pathogenic ★★ 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/clcn7-p-ser9pro (accessed [today's date]).

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