Is CLCN2 p.Phe147Leu (c.441C>G) pathogenic?

CLCN2 p.Phe147Leu (c.441C>G) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-04). AlphaMissense: likely pathogenic (0.9749); Very rare (popmax 0.00223%, eas).

How common is CLCN2 p.Phe147Leu (c.441C>G) in the general population?

CLCN2 p.Phe147Leu (c.441C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CLCN2 p.Phe147Leu (c.441C>G)?

AlphaMissense predicts likely pathogenic (score 0.9749) — an in-silico prediction, not a clinical call.

CLCN2 p.Phe147Leu

c.441C>G · rs1364293163 · VCV2168068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9749	likely pathogenic
REVEL	0.851	moderately pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	29.0	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 0.00223% East Asian · 1/44,888 alleles

Overall 6.84e-05% 1/1,461,856 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: CLCN2
Protein: p.Phe147Leu
Coding: c.441C>G
MANE Select: NM_004366
dbSNP: rs1364293163
Type: single nucleotide variant
Location: chr3:184358222 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 147: an α-helix

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

Similar variants

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
CLCN2 p.Gly24Asp Pathogenic/Likely pathogenic ★★ ⚠ same type
CLCN2 p.Trp570Ter Pathogenic/Likely pathogenic ★★ same type
CLCN2 c.1171-3T>C Uncertain significance ★★ same type
CLCN2 c.1721+4C>T 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/clcn2-p-phe147leu (accessed [today's date]).

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