Is CLDN16 p.Arg79Ter (c.235C>T) pathogenic?

CLDN16 p.Arg79Ter (c.235C>T) is classified Pathogenic in CLDN16 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-05-01). Very rare (popmax 0.000254%, nfe); Associated with renal hypomagnesemia 3.

What condition is associated with CLDN16 p.Arg79Ter (c.235C>T)?

CLDN16 p.Arg79Ter (c.235C>T) is associated with renal hypomagnesemia 3 (ClinVar).

How common is CLDN16 p.Arg79Ter (c.235C>T) in the general population?

CLDN16 p.Arg79Ter (c.235C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

CLDN16 p.Arg79Ter

c.235C>T · rs104893720 · VCV5925

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

renal hypomagnesemia 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 5
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Pangolin	Δ0.35	loss · gain 0.27 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 2.4, phastCons 0.99
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,010 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,868 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.Arg79Ter
Coding: c.235C>T
MANE Select: NM_006580
dbSNP: rs104893720
Type: single nucleotide variant
Location: chr3:190404779 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74
Residue 79: a UniProt-annotated variant site (in homg3; retained in the endoplasmic reticulum and targeted for proteasomal degradation); a UniProt-annotated variant site (in homg3; retained intracellularly with predominant localization in the golgi apparatus and further targeted to lysosomes); a UniProt-annotated variant site (in homg3; retained in the endoplasmic reticulum and targeted for proteasomal degradation; loss of paracellular sodium-selective transport)

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

Disease context

renal hypomagnesemia 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLDN16 p.Arg79Leu Likely pathogenic ★ same residue
CLDN16 p.Arg79Gln Pathogenic same residue
CLDN16 c.217+1G>A Likely pathogenic ★★ same condition
CLDN16 c.217+5G>A Pathogenic/Likely pathogenic ★★ same condition
CLDN16 p.Arg146Cys Pathogenic/Likely pathogenic ★★ same condition
CLDN16 p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLDN16 p.Arg44Ter Pathogenic/Likely pathogenic ★★ same condition
CLDN16 p.Asp35Asn 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/cldn16-p-arg79ter (accessed [today's date]).

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