Is CLCN2 p.Pro734His (c.2201C>A) pathogenic?

CLCN2 p.Pro734His (c.2201C>A) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: likely benign (0.0847); Absent from gnomAD v4.1.

How common is CLCN2 p.Pro734His (c.2201C>A) in the general population?

CLCN2 p.Pro734His (c.2201C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN2 p.Pro734His (c.2201C>A)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

CLCN2 p.Pro734His

c.2201C>A · VCV4767014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 0.57, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	16.92	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN2
Protein: p.Pro734His
Coding: c.2201C>A
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184352753 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB

Full CLCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN2 p.Pro734Ala Uncertain significance ★ ⚠ same residue
CLCN2 p.Pro734Arg Uncertain significance ★ ⚠ same residue
CLCN2 p.Pro734Ser Uncertain significance ★ ⚠ same residue
CLCN2 p.Pro734Thr Uncertain significance ★ ⚠ same residue
CLCN2 c.898+1G>A Likely pathogenic ★★ same type
CLCN2 p.Arg172Gln Pathogenic ★★ same type
CLCN2 p.Arg610Ter Pathogenic/Likely pathogenic ★★ same type
CLCN2 p.Glu619Ter Pathogenic/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/clcn2-p-pro734his (accessed [today's date]).

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