Is CLDN16 p.Phe162Cys (c.485T>G) pathogenic?

CLDN16 p.Phe162Cys (c.485T>G) is classified Uncertain significance in CLDN16 (ClinVar, Single submitter, 3 submitters; last evaluated 2021-03-26). AlphaMissense: likely pathogenic (0.9772); Ultra-rare (popmax 0.0165%, mid); Associated with renal hypomagnesemia 3.

What condition is associated with CLDN16 p.Phe162Cys (c.485T>G)?

CLDN16 p.Phe162Cys (c.485T>G) is associated with renal hypomagnesemia 3, nephrocalcinosis, nephrolithiasis (ClinVar).

How common is CLDN16 p.Phe162Cys (c.485T>G) in the general population?

CLDN16 p.Phe162Cys (c.485T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLDN16 p.Phe162Cys (c.485T>G)?

AlphaMissense predicts likely pathogenic (score 0.9772) — an in-silico prediction, not a clinical call.

CLDN16 p.Phe162Cys

c.485T>G · rs104893726 · VCV5931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9772 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

renal hypomagnesemia 3

Computational evidence

Protein change
AlphaMissense	0.9772	likely pathogenic · top 3% in CLDN16
REVEL	0.91	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F232C vs ClinVar F162C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.84e-05% 1/1,461,882 alleles · ultra-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.Phe162Cys
Coding: c.485T>G
MANE Select: NM_006580
dbSNP: rs104893726
Type: single nucleotide variant
Location: chr3:190408416 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74
Residue 162: 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; localizes at tight junctions when coexpressed with cldn19; displays almost normal interaction with cldn19 yet it prevents functional synergistic effects on ion selectivity)

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

Also linked: nephrocalcinosis nephrolithiasis

Similar variants

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.Arg79Ter Pathogenic ★★ same condition
CLDN16 p.Asp35Asn Likely pathogenic ★★ same condition
CLDN16 p.Gly128Asp Pathogenic/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-phe162cys (accessed [today's date]).

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