Is CLCN7 p.Ser232= (c.696C>T) pathogenic?

CLCN7 p.Ser232= (c.696C>T) is classified Benign in CLCN7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Low-frequency (popmax 1.62%, nfe); Associated with osteopetrosis.

What condition is associated with CLCN7 p.Ser232= (c.696C>T)?

CLCN7 p.Ser232= (c.696C>T) is associated with osteopetrosis, bone disorder (ClinVar).

How common is CLCN7 p.Ser232= (c.696C>T) in the general population?

CLCN7 p.Ser232= (c.696C>T) is low-frequency (popmax 1.62%, nfe) (gnomAD).

CLCN7 p.Ser232=

c.696C>T · rs117183989 · VCV317957

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.62%, nfe)

Conditions

osteopetrosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.1	GERP -3.3
Overall
CADD	1.205	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.62% European (non-Finnish) · 19,084/1,179,898 alleles

Filtering AF 1.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.59%

Overall 1.34% 21,703/1,613,732 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.62%	62
Ashkenazi Jewishnot grpmax-eligible	1.5%	67
Remaining individualsnot grpmax-eligible	1.2%	84
Admixed American	0.868%	115
Middle Eastern	0.858%	117
Finnishnot grpmax-eligible	0.823%	122
African / African-American	0.233%	429
South Asian	0.167%	599
Amishnot grpmax-eligible	0.11%	912
East Asian	0.00446%	22,440

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.Ser232=
Coding: c.696C>T
MANE Select: NM_001287
dbSNP: rs117183989
Type: single nucleotide variant
Location: chr16:1457736 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 232: an α-helix

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

Also linked: bone disorder

Similar variants

CLCN7 p.Arg286Gln Pathogenic/Likely pathogenic ★★ same condition
CLCN7 p.Arg286Trp Pathogenic/Likely pathogenic ★★ same condition
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

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-ser232 (accessed [today's date]).

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