Is CLDN16 p.Ser40Arg (c.120C>G) pathogenic?

CLDN16 p.Ser40Arg (c.120C>G) is classified Pathogenic in CLDN16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). AlphaMissense: likely pathogenic (0.9936); Very rare (popmax 0.000339%, nfe); Associated with CLDN16-related disorder.

What condition is associated with CLDN16 p.Ser40Arg (c.120C>G)?

CLDN16 p.Ser40Arg (c.120C>G) is associated with CLDN16-related disorder (ClinVar).

How common is CLDN16 p.Ser40Arg (c.120C>G) in the general population?

CLDN16 p.Ser40Arg (c.120C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CLDN16 p.Ser40Arg (c.120C>G)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

CLDN16 p.Ser40Arg

c.120C>G · VCV4965511

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

CLDN16-related disorder

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic ✓ concordant with ClinVar · top 1% in CLDN16
REVEL	0.694	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP 1.6, phastCons 0.97
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S110R vs ClinVar S40R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,394 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,228 alleles · very rare

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: CLDN16
Protein: p.Ser40Arg
Coding: c.120C>G
MANE Select: NM_006580
Type: single nucleotide variant
Location: chr3:190402342 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74

Full CLDN16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLDN16-related disorder

Similar variants

CLDN16 p.Ser40Asn Uncertain significance ★ same residue
CLDN16 p.Arg146Cys Pathogenic/Likely pathogenic ★★ same condition
CLDN16 p.Leu81Phe Pathogenic ★★ ⚠ same condition
CLDN16 c.383-1G>C Likely pathogenic ★ same condition
CLDN16 c.-138C>T Likely pathogenic ★ same condition
CLDN16 p.Cys50Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
CLDN16 c.382+5C>T Likely benign same condition
CLDN16 p.Ile8= Likely benign 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/cldn16-p-ser40arg (accessed [today's date]).

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