Is CLDN16 p.Pro110Leu (c.329C>T) pathogenic?

CLDN16 p.Pro110Leu (c.329C>T) is classified Uncertain significance in CLDN16 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-06). AlphaMissense: likely benign (0.2463); Ultra-rare (popmax 0.0548%, afr).

How common is CLDN16 p.Pro110Leu (c.329C>T) in the general population?

CLDN16 p.Pro110Leu (c.329C>T) is ultra-rare (popmax 0.0548%, afr) (gnomAD).

What do computational predictors say about CLDN16 p.Pro110Leu (c.329C>T)?

AlphaMissense predicts likely benign (score 0.2463) — an in-silico prediction, not a clinical call.

CLDN16 p.Pro110Leu

c.329C>T · rs140829596 · VCV1723853

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2463 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0548%, afr)

Computational evidence

Protein change
AlphaMissense	0.2463	likely benign
REVEL	0.564	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 22 kb · p 0.76 · regional, not allelic
Overall
CADD	26.1	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 P180L vs ClinVar P110L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0548% African / African-American · 41/74,868 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00403% 65/1,613,940 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0548%	1,826
Middle Eastern	0.0493%	2,027
Remaining individualsnot grpmax-eligible	0.0112%	8,926
South Asian	0.00659%	15,181
East Asian	0.00446%	22,443
Admixed American	0.00333%	29,987
European (non-Finnish)	0.000339%	295,006

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.Pro110Leu
Coding: c.329C>T
MANE Select: NM_006580
dbSNP: rs140829596
Type: single nucleotide variant
Location: chr3:190404873 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74
Residue 110: 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)

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

Similar variants

CLDN16 c.217+1G>A Likely pathogenic ★★ same type
CLDN16 c.217+5G>A Pathogenic/Likely pathogenic ★★ same type
CLDN16 p.Arg146Cys Pathogenic/Likely pathogenic ★★ same type
CLDN16 p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same type
CLDN16 p.Arg44Ter Pathogenic/Likely pathogenic ★★ same type
CLDN16 p.Arg79Ter Pathogenic ★★ same type
CLDN16 p.Asp35Asn Likely pathogenic ★★ same type
CLDN16 p.Gly128Asp Pathogenic/Likely pathogenic ★★ same type

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-pro110leu (accessed [today's date]).

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