Is CLCN6 p.Asp99= (c.297C>T) pathogenic?

CLCN6 p.Asp99= (c.297C>T) is classified Likely benign in CLCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). Very rare (popmax 0.000339%, nfe).

How common is CLCN6 p.Asp99= (c.297C>T) in the general population?

CLCN6 p.Asp99= (c.297C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

CLCN6 p.Asp99=

c.297C>T · rs745595684 · VCV1672972

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

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 0.32	GERP 0.27, phastCons 0.99
Overall
CADD	7.353	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,018 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)grpmax	0.000339%	295,004

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CLCN6
Protein: p.Asp99=
Coding: c.297C>T
MANE Select: NM_001286
dbSNP: rs745595684
Type: single nucleotide variant
Location: chr1:11819505 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 3 PDB
Residue 99: an α-helix

Full CLCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN6 p.Tyr553Cys Pathogenic ★★ ⚠ same type
CLCN6 p.Ala127Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala144Glu Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala256Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala392Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala527Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala78Val Uncertain significance ★★ ⚠ 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/clcn6-p-asp99 (accessed [today's date]).

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