Is CLDND2 p.Ala136Pro (c.406G>C) pathogenic?

CLDND2 p.Ala136Pro (c.406G>C) is classified Uncertain significance in CLDND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.7702); Ultra-rare (popmax 0.0165%, mid).

How common is CLDND2 p.Ala136Pro (c.406G>C) in the general population?

CLDND2 p.Ala136Pro (c.406G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLDND2 p.Ala136Pro (c.406G>C)?

AlphaMissense predicts likely pathogenic (score 0.7702) — an in-silico prediction, not a clinical call.

CLDND2 p.Ala136Pro

c.406G>C · rs1452170652 · VCV3145544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7702	likely pathogenic · top 6% in CLDND2
REVEL	0.728	pathogenic-leaning
SaProt	LLR -14.61	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 4.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,432 bp · p 0.36 · regional, not allelic
Overall
CADD	26.0	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 0.0165% Middle Eastern · 1/6,052 alleles

Overall 0.000138% 2/1,450,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
European (non-Finnish)	8.52e-05%	1,174,240

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: CLDND2
Protein: p.Ala136Pro
Coding: c.406G>C
MANE Select: NM_152353
dbSNP: rs1452170652
Type: single nucleotide variant
Location: chr19:51367481 (GRCh38)
Gene constraint: LOEUF 1.58 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.58

Full CLDND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLDND2 p.Thr157= Likely benign ★★ same type
CLDND2 p.Ala64Val Uncertain significance ★ ⚠ same type
CLDND2 p.Arg33Cys Uncertain significance ★ ⚠ same type
CLDND2 p.Arg5Trp Uncertain significance ★ ⚠ same type
CLDND2 p.Arg92Gln Uncertain significance ★ ⚠ same type
CLDND2 p.Cys55Phe Uncertain significance ★ ⚠ same type
CLDND2 p.Glu89Lys Uncertain significance ★ ⚠ same type
CLDND2 p.Gly10Glu 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/cldnd2-p-ala136pro (accessed [today's date]).

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