Is CLCN7 p.Val778Phe (c.2332G>T) pathogenic?

CLCN7 p.Val778Phe (c.2332G>T) is classified Likely pathogenic in CLCN7 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-06-20). AlphaMissense: likely pathogenic (0.9881); Absent from gnomAD v4.1; Associated with autosomal recessive osteopetrosis 4.

What condition is associated with CLCN7 p.Val778Phe (c.2332G>T)?

CLCN7 p.Val778Phe (c.2332G>T) is associated with autosomal recessive osteopetrosis 4 (ClinVar).

How common is CLCN7 p.Val778Phe (c.2332G>T) in the general population?

CLCN7 p.Val778Phe (c.2332G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN7 p.Val778Phe (c.2332G>T)?

AlphaMissense predicts likely pathogenic (score 0.9881) — an in-silico prediction, not a clinical call.

CLCN7 p.Val778Phe

c.2332G>T · rs1172932679 · VCV1172575

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9881 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive osteopetrosis 4

Computational evidence

Protein change
AlphaMissense	0.9881	likely pathogenic ✓ concordant with ClinVar
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -14.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.49	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 1.8e-09 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN7
Protein: p.Val778Phe
Coding: c.2332G>T
MANE Select: NM_001287
dbSNP: rs1172932679
Type: single nucleotide variant
Location: chr16:1446717 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 778: a β-strand; the cbs 2 domain

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

Disease context

autosomal recessive osteopetrosis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN7 c.1448-2A>G Likely pathogenic ★★ same condition
CLCN7 c.1617+119G>A Pathogenic ★★ same condition
CLCN7 c.739-18G>A Pathogenic/Likely pathogenic ★★ same condition
CLCN7 p.Arg286Gln Pathogenic/Likely pathogenic ★★ same condition
CLCN7 p.Arg762Trp Pathogenic/Likely pathogenic ★★ same condition
CLCN7 p.Arg767Trp Pathogenic ★★ same condition
CLCN7 p.Gln47Ter Pathogenic ★★ same condition
CLCN7 p.Trp398Ter Pathogenic/Likely pathogenic ★★ 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-val778phe (accessed [today's date]).

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