Is CTNND2 p.Pro335Arg (c.1004C>G) pathogenic?

CTNND2 p.Pro335Arg (c.1004C>G) is classified Uncertain significance in CTNND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.3844); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with CTNND2 p.Pro335Arg (c.1004C>G)?

CTNND2 p.Pro335Arg (c.1004C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTNND2 p.Pro335Arg (c.1004C>G) in the general population?

CTNND2 p.Pro335Arg (c.1004C>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CTNND2 p.Pro335Arg (c.1004C>G)?

AlphaMissense predicts ambiguous (score 0.3844) — an in-silico prediction, not a clinical call.

CTNND2 p.Pro335Arg

c.1004C>G · VCV4616705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3844	ambiguous
REVEL	0.5	indeterminate
SaProt	LLR -5.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 557 kb · p 0.95 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,936 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00223% 36/1,612,964 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,968
Remaining individualsnot grpmax-eligible	0.0032%	31,202
European (non-Finnish)	0.00271%	36,865

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: CTNND2
Protein: p.Pro335Arg
Coding: c.1004C>G
MANE Select: NM_001332
Type: single nucleotide variant
Location: chr5:11384838 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 58.88

Full CTNND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTNND2 p.Asp700Gly Uncertain significance ★★ ⚠ same condition
CTNND2 p.Asp802Asn Uncertain significance ★★ ⚠ same condition
CTNND2 p.Glu217Asp Uncertain significance ★★ ⚠ same condition
CTNND2 p.Ala251Thr Benign/Likely benign ★★ ⚠ same condition
CTNND2 p.Arg427Cys Likely benign ★★ ⚠ same condition
CTNND2 p.Arg454Cys Likely benign ★★ ⚠ same condition
CTNND2 p.Glu26Gln Benign/Likely benign ★★ same condition
CTNND2 p.Gly1104Ser Benign/Likely benign ★★ 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/ctnnd2-p-pro335arg (accessed [today's date]).

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