Is CLDN5 p.Pro112Arg (c.335C>G) pathogenic?

CLDN5 p.Pro112Arg (c.335C>G) is classified Likely benign in CLDN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0861); Very rare (popmax 0.0057%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLDN5 p.Pro112Arg (c.335C>G)?

CLDN5 p.Pro112Arg (c.335C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLDN5 p.Pro112Arg (c.335C>G) in the general population?

CLDN5 p.Pro112Arg (c.335C>G) is very rare (popmax 0.0057%, nfe) (gnomAD).

What do computational predictors say about CLDN5 p.Pro112Arg (c.335C>G)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

CLDN5 p.Pro112Arg

c.335C>G · VCV3493435

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0057%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 441 bp · p 0.0013 · regional, not allelic
Overall
CADD	19.15	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 0.0057% European (non-Finnish) · 67/1,175,930 alleles

Filtering AF 0.00455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00418%

Overall 0.00451% 72/1,597,984 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0057%	17,551
African / African-American	0.00535%	18,691
Remaining individualsnot grpmax-eligible	0.00161%	62,042

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: CLDN5
Protein: p.Pro112Arg
Coding: c.335C>G
MANE Select: NM_001363066
Type: single nucleotide variant
Location: chr22:19523921 (GRCh38)
Gene constraint: LOEUF 1.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42

Full CLDN5 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

Similar variants

CLDN5 p.Gly60Arg Pathogenic ★★ same condition
CLDN5 c.-104G>T Uncertain significance ★ same condition
CLDN5 c.-131C>A Uncertain significance ★ same condition
CLDN5 c.-29G>A Uncertain significance ★ same condition
CLDN5 c.-48G>A Uncertain significance ★ same condition
CLDN5 c.-6C>G Uncertain significance ★ same condition
CLDN5 c.-93G>C Uncertain significance ★ same condition
CLDN5 p.Ala4Thr Uncertain significance ★ ⚠ 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/cldn5-p-pro112arg (accessed [today's date]).

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