Is CLCN3 p.Pro488Ser (c.1462C>T) pathogenic?

CLCN3 p.Pro488Ser (c.1462C>T) is classified Uncertain significance in CLCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-10). AlphaMissense: likely benign (0.2719); Very rare (popmax 0.00267%, afr).

How common is CLCN3 p.Pro488Ser (c.1462C>T) in the general population?

CLCN3 p.Pro488Ser (c.1462C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CLCN3 p.Pro488Ser (c.1462C>T)?

AlphaMissense predicts likely benign (score 0.2719) — an in-silico prediction, not a clinical call.

CLCN3 p.Pro488Ser

c.1462C>T · VCV4083040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2719	likely benign
REVEL	0.629	indeterminate
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 12 kb · p 1.5e-15 · regional, not allelic
Overall
CADD	22.4	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 0.00267% African / African-American · 2/74,900 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,450
European (non-Finnish)	8.48e-05%	1,179,864

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: CLCN3
Protein: p.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_001829
Type: single nucleotide variant
Location: chr4:169697633 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.95 · 5 PDB

Full CLCN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN3 p.Pro488Ala Uncertain significance ★ ⚠ same residue
CLCN3 p.Ile607Val Likely pathogenic ★★ same type
CLCN3 p.Thr570Ile Likely pathogenic ★★ ⚠ same type
CLCN3 p.Val324Ala Likely pathogenic ★★ same type
CLCN3 c.2367-2099A>C Uncertain significance ★★ same type
CLCN3 p.Asn788Ser Uncertain significance ★★ ⚠ same type
CLCN3 p.Asp485Asn Uncertain significance ★★ ⚠ same type
CLCN3 p.Lys186Glu 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/clcn3-p-pro488ser (accessed [today's date]).

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