Is CLDN14 p.Pro74Arg (c.221C>G) pathogenic?

CLDN14 p.Pro74Arg (c.221C>G) is classified Uncertain significance in CLDN14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.7134); Very rare (popmax 0.000508%, nfe).

How common is CLDN14 p.Pro74Arg (c.221C>G) in the general population?

CLDN14 p.Pro74Arg (c.221C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CLDN14 p.Pro74Arg (c.221C>G)?

AlphaMissense predicts likely pathogenic (score 0.7134) — an in-silico prediction, not a clinical call.

CLDN14 p.Pro74Arg

c.221C>G · VCV4537949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7134	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -12.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 716 bp · p 0.098 · regional, not allelic
Overall
CADD	28.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,008 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,294 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: CLDN14
Protein: p.Pro74Arg
Coding: c.221C>G
MANE Select: NM_001146079
Type: single nucleotide variant
Location: chr21:36461475 (GRCh38)
Gene constraint: LOEUF 1.745 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.00

Full CLDN14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDN14 p.Pro74Leu Uncertain significance ★★ ⚠ same residue
CLDN14 p.Pro74His Uncertain significance ★ ⚠ same residue
CLDN14 p.Arg81His Pathogenic/Likely pathogenic ★★ same type
CLDN14 p.Cys97Ter Pathogenic/Likely pathogenic ★★ same type
CLDN14 p.Trp30Ter Pathogenic/Likely pathogenic ★★ same type
CLDN14 c.*107G>A Uncertain significance ★★ same type
CLDN14 p.Ala196Val Uncertain significance ★★ ⚠ same type
CLDN14 p.Ala72Val Uncertain significance ★★ ⚠ 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/cldn14-p-pro74arg (accessed [today's date]).

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