Is CLCN7 p.Pro249Arg (c.746C>G) pathogenic?

CLCN7 p.Pro249Arg (c.746C>G) is classified Pathogenic/Likely pathogenic in CLCN7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 8.48e-05%, nfe).

How common is CLCN7 p.Pro249Arg (c.746C>G) in the general population?

CLCN7 p.Pro249Arg (c.746C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CLCN7 p.Pro249Arg (c.746C>G)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

CLCN7 p.Pro249Arg

c.746C>G · rs2038850050 · VCV2736273

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar · top 5% in CLCN7
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -17.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 1.8e-09 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,846 alleles

Overall 6.84e-05% 1/1,461,274 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.Pro249Arg
Coding: c.746C>G
MANE Select: NM_001287
dbSNP: rs2038850050
Type: single nucleotide variant
Location: chr16:1457330 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 249: a UniProt-annotated variant site (in optb4); an α-helix

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

Similar variants

CLCN7 p.Pro249Leu Pathogenic ★★ same residue
CLCN7 p.Pro249= Likely benign ★★ same residue
CLCN7 p.Pro249Gln Likely pathogenic ★ same residue
CLCN7 c.1448-2A>G Likely pathogenic ★★ same type
CLCN7 c.1617+119G>A Pathogenic ★★ same type
CLCN7 c.739-18G>A Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Gln Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Trp 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/clcn7-p-pro249arg (accessed [today's date]).

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