Is CLCN4 p.Pro607Leu (c.1820C>T) pathogenic?

CLCN4 p.Pro607Leu (c.1820C>T) is classified Conflicting classifications of pathogenicity in CLCN4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-17). AlphaMissense: likely benign (0.0771); Very rare (popmax 0.00296%, eas); Associated with Inborn genetic diseases.

What condition is associated with CLCN4 p.Pro607Leu (c.1820C>T)?

CLCN4 p.Pro607Leu (c.1820C>T) is associated with Inborn genetic diseases, intellectual disability, X-linked 49 (ClinVar).

How common is CLCN4 p.Pro607Leu (c.1820C>T) in the general population?

CLCN4 p.Pro607Leu (c.1820C>T) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about CLCN4 p.Pro607Leu (c.1820C>T)?

AlphaMissense predicts likely benign (score 0.0771) — an in-silico prediction, not a clinical call.

CLCN4 p.Pro607Leu

c.1820C>T · rs1042357480 · VCV1360558

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0771	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 6,907 bp · p 0.001 · regional, not allelic
Overall
CADD	21.9	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 0.00296% East Asian · 1/33,777 alleles

Filtering AF 0.00202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00172%

Overall 0.0024% 29/1,210,659 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0042%	23,799
East Asiangrpmax	0.00296%	33,777
European (non-Finnish)	0.0029%	34,436

Remaining individuals 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: CLCN4
Protein: p.Pro607Leu
Coding: c.1820C>T
MANE Select: NM_001830
dbSNP: rs1042357480
Type: single nucleotide variant
Location: chrX:10213924 (GRCh38)
Structure: AlphaFold pLDDT 84.66
Residue 607: the cbs 1 domain

Full CLCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, X-linked 49

Similar variants

CLCN4 p.Pro607Gln Uncertain significance ★★ ⚠ same residue
CLCN4 p.Pro607Ser Benign/Likely benign ★★ ⚠ same residue
CLCN4 p.Pro607= Likely benign ★ same residue
CLCN4 p.Ala555Val Pathogenic ★★ same condition
CLCN4 p.Arg718Trp Pathogenic ★★ same condition
CLCN4 p.Gly467Ser Likely pathogenic ★★ same condition
CLCN4 p.Gly544Arg Pathogenic ★★ same condition
CLCN4 p.Val317Ile 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/clcn4-p-pro607leu (accessed [today's date]).

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