Is CLCN7 p.Val593Met (c.1777G>A) pathogenic?

CLCN7 p.Val593Met (c.1777G>A) is classified Uncertain significance in CLCN7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: ambiguous (0.387); Very rare (popmax 0.00167%, amr).

How common is CLCN7 p.Val593Met (c.1777G>A) in the general population?

CLCN7 p.Val593Met (c.1777G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CLCN7 p.Val593Met (c.1777G>A)?

AlphaMissense predicts ambiguous (score 0.387) — an in-silico prediction, not a clinical call.

CLCN7 p.Val593Met

c.1777G>A · rs778420950 · VCV1400996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.387	ambiguous
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -8.07	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 1.8e-09 · regional, not allelic
Overall
CADD	27.8	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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000124% 2/1,612,604 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	8.47e-05%	1,180,013

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.Val593Met
Coding: c.1777G>A
MANE Select: NM_001287
dbSNP: rs778420950
Type: single nucleotide variant
Location: chr16:1448986 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB
Residue 593: an α-helix

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

Similar variants

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CLCN7 c.739-18G>A Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Gln Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg286Trp Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg526Gln Likely pathogenic ★★ same type
CLCN7 p.Arg526Trp Pathogenic/Likely pathogenic ★★ same type
CLCN7 p.Arg55Ter Pathogenic/Likely pathogenic ★★ same type

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-val593met (accessed [today's date]).

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