Is CLCN7 p.Ser5Phe (c.14C>T) pathogenic?

CLCN7 p.Ser5Phe (c.14C>T) is classified Uncertain significance in CLCN7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4347); Very rare (popmax 0.000267%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLCN7 p.Ser5Phe (c.14C>T)?

CLCN7 p.Ser5Phe (c.14C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN7 p.Ser5Phe (c.14C>T) in the general population?

CLCN7 p.Ser5Phe (c.14C>T) is very rare (popmax 0.000267%, nfe) (gnomAD).

What do computational predictors say about CLCN7 p.Ser5Phe (c.14C>T)?

AlphaMissense predicts ambiguous (score 0.4347) — an in-silico prediction, not a clinical call.

CLCN7 p.Ser5Phe

c.14C>T · rs745864670 · VCV1365720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000267%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4347	ambiguous
REVEL	0.487	indeterminate
SaProt	LLR -7.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 0.33, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 13 kb · p 0.031 · regional, not allelic
Overall
CADD	25.3	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 0.000267% European (non-Finnish) · 3/1,124,230 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000201% 3/1,489,350 alleles · very rare

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: CLCN7
Protein: p.Ser5Phe
Coding: c.14C>T
MANE Select: NM_001287
dbSNP: rs745864670
Type: single nucleotide variant
Location: chr16:1474961 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 5: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN7 p.Ala131Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala259Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala464Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala673Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala714Thr Uncertain significance ★★ same condition
CLCN7 p.Arg223Trp Uncertain significance ★★ ⚠ same condition
CLCN7 p.Arg25Gln Uncertain significance ★★ ⚠ same condition

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-ser5phe (accessed [today's date]).

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