Is CDH15 p.Arg772His (c.2315G>A) pathogenic?

CDH15 p.Arg772His (c.2315G>A) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.4975); Ultra-rare (popmax 0.0331%, mid).

How common is CDH15 p.Arg772His (c.2315G>A) in the general population?

CDH15 p.Arg772His (c.2315G>A) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about CDH15 p.Arg772His (c.2315G>A)?

AlphaMissense predicts ambiguous (score 0.4975) — an in-silico prediction, not a clinical call.

CDH15 p.Arg772His

c.2315G>A · VCV4651039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4975	ambiguous
REVEL	0.735	pathogenic-leaning
SaProt	LLR -12.19	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	28.7	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 0.0331% Middle Eastern · 2/6,048 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.0044% 71/1,612,314 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,024
South Asian	0.00989%	10,114
East Asian	0.00669%	14,956
European (non-Finnish)	0.00441%	22,688
Admixed American	0.00333%	29,986
African / African-American	0.00267%	37,522
Finnishnot grpmax-eligible	0.0016%	62,638

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.Arg772His
Coding: c.2315G>A
MANE Select: NM_004933
Type: single nucleotide variant
Location: chr16:89195025 (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

CDH3 p.Pro772Leu Uncertain significance ★★ ⚠ same residue
CDH3 p.Pro772= Likely benign ★ 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-arg772his (accessed [today's date]).

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