Is CLCN7 p.Pro30= (c.90C>T) pathogenic?

CLCN7 p.Pro30= (c.90C>T) is classified Conflicting classifications of pathogenicity in CLCN7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-07). Rare (popmax 0.322%, afr); Associated with osteopetrosis.

What condition is associated with CLCN7 p.Pro30= (c.90C>T)?

CLCN7 p.Pro30= (c.90C>T) is associated with osteopetrosis (ClinVar).

How common is CLCN7 p.Pro30= (c.90C>T) in the general population?

CLCN7 p.Pro30= (c.90C>T) is rare (popmax 0.322%, afr) (gnomAD).

CLCN7 p.Pro30=

c.90C>T · rs550851648 · VCV317970

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.322%, afr)

Conditions

osteopetrosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -2.7
Overall
CADD	8.119	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.322% African / African-American · 218/67,604 alleles

Filtering AF 0.287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.274%

Overall 0.0162% 235/1,449,878 alleles · rare exomes 98/1,297,880 · genomes 137/151,998 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.322%	310
Remaining individualsnot grpmax-eligible	0.018%	5,557
Admixed American	0.0122%	8,220
Finnishnot grpmax-eligible	0.00236%	42,348
European (non-Finnish)	9.06e-05%	1,103,568

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.Pro30=
Coding: c.90C>T
MANE Select: NM_001287
dbSNP: rs550851648
Type: single nucleotide variant
Location: chr16:1474885 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 30: the 'disordered' region

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

Disease context

osteopetrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN7 c.*130G>A Uncertain significance ★★ same condition
CLCN7 p.Arg674Leu Uncertain significance ★★ ⚠ same condition
CLCN7 p.Arg717His Uncertain significance ★★ ⚠ same condition
CLCN7 p.Gly233Ser Uncertain significance ★★ ⚠ same condition
CLCN7 p.His85Tyr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ile379Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ile569Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Lys274Arg 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-pro30 (accessed [today's date]).

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