Is CLCN4 p.Pro607Ser (c.1819C>T) pathogenic?

CLCN4 p.Pro607Ser (c.1819C>T) is classified Benign/Likely benign in CLCN4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-26). AlphaMissense: likely benign (0.0856); Rare (popmax 0.776%, eas); Associated with microcephaly.

What condition is associated with CLCN4 p.Pro607Ser (c.1819C>T)?

CLCN4 p.Pro607Ser (c.1819C>T) is associated with microcephaly (ClinVar).

How common is CLCN4 p.Pro607Ser (c.1819C>T) in the general population?

CLCN4 p.Pro607Ser (c.1819C>T) is rare (popmax 0.776%, eas) (gnomAD).

What do computational predictors say about CLCN4 p.Pro607Ser (c.1819C>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

CLCN4 p.Pro607Ser

c.1819C>T · rs193252755 · VCV696782

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.776%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

microcephaly

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -7.76	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 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 6,907 bp · p 0.001 · regional, not allelic
Overall
CADD	21.7	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 0.776% East Asian · 262/33,772 alleles

Filtering AF 0.699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.669%

Overall 0.0225% 272/1,210,613 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.776%	129
Remaining individualsnot grpmax-eligible	0.0147%	6,801
European (non-Finnish)	0.000335%	298,424

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.Pro607Ser
Coding: c.1819C>T
MANE Select: NM_001830
dbSNP: rs193252755
Type: single nucleotide variant
Location: chrX:10213923 (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

microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN4 p.Pro607Gln Uncertain significance ★★ ⚠ same residue
CLCN4 p.Pro607Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CLCN4 p.Pro607= Likely benign ★ same residue
CLCN4 c.844-1G>A Pathogenic/Likely pathogenic ★★ same type
CLCN4 p.Ala555Val Pathogenic ★★ ⚠ same type
CLCN4 p.Arg718Trp Pathogenic ★★ same type
CLCN4 p.Asp89Asn Pathogenic/Likely pathogenic ★★ ⚠ same type
CLCN4 p.Gly467Ser 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/clcn4-p-pro607ser (accessed [today's date]).

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