Is CDH15 p.Ala122Val (c.365C>T) pathogenic?

CDH15 p.Ala122Val (c.365C>T) is classified Likely benign in CDH15 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2017-07-18). AlphaMissense: likely benign (0.2878); Rare (popmax 0.209%, afr); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Ala122Val (c.365C>T)?

CDH15 p.Ala122Val (c.365C>T) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Ala122Val (c.365C>T) in the general population?

CDH15 p.Ala122Val (c.365C>T) is rare (popmax 0.209%, afr) (gnomAD).

What do computational predictors say about CDH15 p.Ala122Val (c.365C>T)?

AlphaMissense predicts likely benign (score 0.2878) — an in-silico prediction, not a clinical call.

CDH15 p.Ala122Val

c.365C>T · rs121434541 · VCV17644

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2878 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.209%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.2878	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -1, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	25.3	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 0.209% African / African-American · 157/75,062 alleles

Filtering AF 0.182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.172%

Overall 0.0139% 224/1,614,124 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.209%	478
Middle Eastern	0.033%	3,031
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0128%	7,813
South Asian	0.00549%	18,217
European (non-Finnish)	0.00331%	30,257
East Asian	0.00223%	44,892

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: CDH15
Protein: p.Ala122Val
Coding: c.365C>T
MANE Select: NM_004933
dbSNP: rs121434541
Type: single nucleotide variant
Location: chr16:89183555 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 122: a UniProt-annotated variant site (in mrd3; affects cell-cell adhesion but not surface expression of the protein); the cadherin 1 domain

Full CDH15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH15 p.Ala122Pro Uncertain significance ★ ⚠ same residue
CDH15 p.Arg92Trp Uncertain significance ★★ ⚠ same condition
CDH15 p.Gly514Arg Uncertain significance ★★ ⚠ same condition
CDH15 p.Pro347Leu Uncertain significance ★★ ⚠ same condition
CDH15 p.Pro347Ser Uncertain significance ★★ ⚠ same condition
CDH15 p.Thr158Ala Uncertain significance ★★ ⚠ same condition
CDH15 p.Val43Leu Uncertain significance ★★ ⚠ same condition
CDH15 p.Arg60Cys 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/cdh15-p-ala122val (accessed [today's date]).

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