Is CLDN1 p.Arg197Ser (c.591G>T) pathogenic?

CLDN1 p.Arg197Ser (c.591G>T) is classified Uncertain significance in CLDN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: ambiguous (0.39); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CLDN1 p.Arg197Ser (c.591G>T)?

CLDN1 p.Arg197Ser (c.591G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLDN1 p.Arg197Ser (c.591G>T) in the general population?

CLDN1 p.Arg197Ser (c.591G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLDN1 p.Arg197Ser (c.591G>T)?

AlphaMissense predicts ambiguous (score 0.39) — an in-silico prediction, not a clinical call.

CLDN1 p.Arg197Ser

c.591G>T · rs201612869 · VCV2283542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.39 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.39	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -6.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.24 · regional, not allelic
Overall
CADD	19.58	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLDN1
Protein: p.Arg197Ser
Coding: c.591G>T
MANE Select: NM_021101
dbSNP: rs201612869
Type: single nucleotide variant
Location: chr3:190308322 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 197: the 'disordered' region

Full CLDN1 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

CLDN1 p.Arg188Gln Uncertain significance ★★ ⚠ same condition
CLDN1 p.Pro202Leu Uncertain significance ★★ ⚠ same condition
CLDN1 p.Pro204Thr Uncertain significance ★★ ⚠ same condition
CLDN1 p.Val145Ile Uncertain significance ★★ ⚠ same condition
CLDN1 p.Val155Ala Uncertain significance ★★ ⚠ same condition
CLDN1 p.Ala124Val Conflicting classifications of pathogenicity ★ ⚠ same condition
CLDN1 p.Ala138Val Uncertain significance ★ ⚠ same condition
CLDN1 p.Ala14Asp 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/cldn1-p-arg197ser (accessed [today's date]).

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