Is CDH15 p.Ser744Trp (c.2231C>G) pathogenic?

CDH15 p.Ser744Trp (c.2231C>G) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely pathogenic (0.6892); Ultra-rare (popmax 0.0158%, nfe).

How common is CDH15 p.Ser744Trp (c.2231C>G) in the general population?

CDH15 p.Ser744Trp (c.2231C>G) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about CDH15 p.Ser744Trp (c.2231C>G)?

AlphaMissense predicts likely pathogenic (score 0.6892) — an in-silico prediction, not a clinical call.

CDH15 p.Ser744Trp

c.2231C>G · rs145092759 · VCV3141122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6892	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -14.31	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 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	25.8	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 0.0158% European (non-Finnish) · 186/1,178,076 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.0126% 202/1,608,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0158%	6,334
African / African-American	0.00801%	12,491
Admixed American	0.00672%	14,889
Remaining individualsnot grpmax-eligible	0.00642%	15,572
Finnishnot grpmax-eligible	0.00161%	62,178
South Asian	0.00111%	90,334

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.Ser744Trp
Coding: c.2231C>G
MANE Select: NM_004933
dbSNP: rs145092759
Type: single nucleotide variant
Location: chr16:89194941 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70

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

Similar variants

CDH15 p.Ser744Leu Uncertain significance ★★ ⚠ same residue
CDH3 p.Tyr744His Uncertain significance ★ ⚠ same residue
CDH3 c.1796-2A>G Pathogenic ★★ same type
CDH3 c.691+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH3 p.Arg103Ter Pathogenic ★★ same type
CDH3 p.Arg221Ter Pathogenic ★★ same type
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same type
CDH3 p.Gln299Ter 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/cdh15-p-ser744trp (accessed [today's date]).

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