Is CLCN7 p.Phe718= (c.2154C>T) pathogenic?

CLCN7 p.Phe718= (c.2154C>T) is classified Conflicting classifications of pathogenicity in CLCN7 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0408%, amr); Associated with osteopetrosis.

What condition is associated with CLCN7 p.Phe718= (c.2154C>T)?

CLCN7 p.Phe718= (c.2154C>T) is associated with osteopetrosis (ClinVar).

How common is CLCN7 p.Phe718= (c.2154C>T) in the general population?

CLCN7 p.Phe718= (c.2154C>T) is ultra-rare (popmax 0.0408%, amr) (gnomAD).

CLCN7 p.Phe718=

c.2154C>T · rs145775350 · VCV317944

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0408%, amr)

Conditions

osteopetrosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 0.39, phastCons 1
Overall
CADD	8.257	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0408% Admixed American · 21/51,502 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0304% 472/1,553,196 alleles · ultra-rare exomes 425/1,400,960 · genomes 47/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0408%	2,452
European (non-Finnish)	0.0371%	2,696
Remaining individualsnot grpmax-eligible	0.0266%	3,762
African / African-American	0.00957%	10,452
Finnishnot grpmax-eligible	0.00341%	29,357

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.Phe718=
Coding: c.2154C>T
MANE Select: NM_001287
dbSNP: rs145775350
Type: single nucleotide variant
Location: chr16:1447488 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 718: 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

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-phe718 (accessed [today's date]).

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