Is CLCN2 p.Asp90His (c.268G>C) pathogenic?

CLCN2 p.Asp90His (c.268G>C) is classified Conflicting classifications of pathogenicity in CLCN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-07). AlphaMissense: likely pathogenic (0.9972); Rare (popmax 0.154%, eas).

How common is CLCN2 p.Asp90His (c.268G>C) in the general population?

CLCN2 p.Asp90His (c.268G>C) is rare (popmax 0.154%, eas) (gnomAD).

What do computational predictors say about CLCN2 p.Asp90His (c.268G>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

CLCN2 p.Asp90His

c.268G>C · rs117247760 · VCV1537500

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 5% in CLCN2
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	30.0	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

Grpmax group 0.154% East Asian · 69/44,790 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00726% 117/1,610,804 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.154%	649
Remaining individualsnot grpmax-eligible	0.0481%	2,079
African / African-American	0.0147%	6,817
Admixed American	0.00672%	14,878
South Asian	0.00111%	90,444
European (non-Finnish)	0.00017%	589,206

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: CLCN2
Protein: p.Asp90His
Coding: c.268G>C
MANE Select: NM_004366
dbSNP: rs117247760
Type: single nucleotide variant
Location: chr3:184358766 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 90: an α-helix

Full CLCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN2 c.898+1G>A Likely pathogenic ★★ same type
CLCN2 p.Arg172Gln Pathogenic ★★ same type
CLCN2 p.Arg610Ter Pathogenic/Likely pathogenic ★★ same type
CLCN2 p.Glu619Ter Pathogenic/Likely pathogenic ★★ same type
CLCN2 p.Gly24Asp Pathogenic/Likely pathogenic ★★ ⚠ same type
CLCN2 p.Trp570Ter Pathogenic/Likely pathogenic ★★ same type
CLCN2 c.1171-3T>C Uncertain significance ★★ same type
CLCN2 c.1721+4C>T 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/clcn2-p-asp90his (accessed [today's date]).

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