Is CLCN5 p.Pro741Ser (c.2221C>T) pathogenic?

CLCN5 p.Pro741Ser (c.2221C>T) is classified Uncertain significance in CLCN5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-26). AlphaMissense: likely benign (0.0742); Very rare (popmax 0.00176%, sas); Associated with Inborn genetic diseases.

What condition is associated with CLCN5 p.Pro741Ser (c.2221C>T)?

CLCN5 p.Pro741Ser (c.2221C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN5 p.Pro741Ser (c.2221C>T) in the general population?

CLCN5 p.Pro741Ser (c.2221C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

What do computational predictors say about CLCN5 p.Pro741Ser (c.2221C>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

CLCN5 p.Pro741Ser

c.2221C>T · rs369687094 · VCV2606292

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 12 kb · p 1.3e-15 · regional, not allelic
Overall
CADD	20.2	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 0.00176% South Asian · 1/56,867 alleles

Filtering AF 0.00066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.00109% 12/1,096,991 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,867
European (non-Finnish)	0.00123%	81,329

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: CLCN5
Protein: p.Pro741Ser
Coding: c.2221C>T
MANE Select: NM_001127898
dbSNP: rs369687094
Type: single nucleotide variant
Location: chrX:50090747 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB

Full CLCN5 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

CLCN5 p.Pro741Leu Uncertain significance ★★ ⚠ same residue
CLCN5 p.Ala319Val Uncertain significance ★★ ⚠ same condition
CLCN5 p.Ala806Val Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg372Cys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg408Cys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg696Trp Uncertain significance ★★ ⚠ same condition
CLCN5 p.Glu176Lys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Glu474Asp 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/clcn5-p-pro741ser (accessed [today's date]).

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