Is CDH15 p.Gln657= (c.1971A>G) pathogenic?

CDH15 p.Gln657= (c.1971A>G) is classified Benign in CDH15 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-07-14). Common (popmax 79%, eas) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Gln657= (c.1971A>G)?

CDH15 p.Gln657= (c.1971A>G) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

CDH15 p.Gln657=

Q: How common is CDH15 p.Gln657= (c.1971A>G) in the general population?

CDH15 p.Gln657= (c.1971A>G) is common (popmax 79%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1971A>G · rs3815615 · VCV128647

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 79%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -2.2, phastCons 1
Overall
CADD	8.039	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 79% East Asian · 35,119/44,452 alleles

Filtering AF 78.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 78%

Overall 44.7% 714,489/1,597,498 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	79%	1
South Asian	54.7%	2
Finnishnot grpmax-eligible	52.9%	2
Remaining individualsnot grpmax-eligible	45.3%	2
Middle Eastern	44%	2
European (non-Finnish)	43.3%	2
Ashkenazi Jewishnot grpmax-eligible	39.6%	3
Admixed American	37.2%	3
African / African-American	35.9%	3
Amishnot grpmax-eligible	34.8%	3

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.Gln657=
Coding: c.1971A>G
MANE Select: NM_004933
dbSNP: rs3815615
Type: single nucleotide variant
Location: chr16:89193585 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 657: the 'disordered' region

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.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.Ala122Val Likely benign ★★ ⚠ 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-gln657 (accessed [today's date]).

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