Is CLCN7 p.Pro80Arg (c.239C>G) pathogenic?

CLCN7 p.Pro80Arg (c.239C>G) is classified Conflicting classifications of pathogenicity in CLCN7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1007); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLCN7 p.Pro80Arg (c.239C>G)?

CLCN7 p.Pro80Arg (c.239C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN7 p.Pro80Arg (c.239C>G) in the general population?

CLCN7 p.Pro80Arg (c.239C>G) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CLCN7 p.Pro80Arg (c.239C>G)?

AlphaMissense predicts likely benign (score 0.1007) — an in-silico prediction, not a clinical call.

CLCN7 p.Pro80Arg

c.239C>G · rs368173900 · VCV2066342

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1007	likely benign
REVEL	0.482	indeterminate
SaProt	LLR -6.34	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 13 kb · p 0.031 · regional, not allelic
Overall
CADD	26.3	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 0.00934% African / African-American · 7/74,926 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00118% 19/1,614,032 alleles · very rare exomes 13/1,461,838 · genomes 6/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,704
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000932%	107,276

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.Pro80Arg
Coding: c.239C>G
MANE Select: NM_001287
dbSNP: rs368173900
Type: single nucleotide variant
Location: chr16:1461649 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB

Full CLCN7 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

CLCN7 p.Pro80Leu Uncertain significance ★★ ⚠ same residue
CLCN7 p.Pro80Thr Uncertain significance ★ ⚠ same residue
CLCN7 p.Pro80= Likely benign ★ same residue
CLCN7 p.Ala131Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala259Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala464Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala673Val 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/clcn7-p-pro80arg (accessed [today's date]).

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