Is CDH4 p.Lys625Arg (c.1874A>G) pathogenic?

CDH4 p.Lys625Arg (c.1874A>G) is classified Benign in CDH4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). AlphaMissense: likely benign (0.0704); Common (popmax 85.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with CDH4-related disorder.

What condition is associated with CDH4 p.Lys625Arg (c.1874A>G)?

CDH4 p.Lys625Arg (c.1874A>G) is associated with CDH4-related disorder (ClinVar).

What do computational predictors say about CDH4 p.Lys625Arg (c.1874A>G)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

CDH4 p.Lys625Arg

Q: How common is CDH4 p.Lys625Arg (c.1874A>G) in the general population?

CDH4 p.Lys625Arg (c.1874A>G) is common (popmax 85.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1874A>G · rs6142884 · VCV3060356

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 85.7%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.1	GERP -4.2, phastCons 0.23
Regional constraint	o/e 0.77	unconstrained · MANE · 160 kb · p 4.6e-12 · regional, not allelic
Overall
CADD	3.9	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 85.7% East Asian · 38,480/44,878 alleles

Filtering AF 85% ClinGen BA1/BS1 input FAF95, joint · FAF99 84.7%

Overall 53.2% 855,865/1,610,020 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	85.7%	1
South Asian	68.7%	1
Admixed American	63.9%	2
Finnishnot grpmax-eligible	58.6%	2
Remaining individualsnot grpmax-eligible	53.3%	2
European (non-Finnish)	51.4%	2
Middle Eastern	50.5%	2
Ashkenazi Jewishnot grpmax-eligible	49.1%	2
Amishnot grpmax-eligible	46.6%	2
African / African-American	31.5%	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: CDH4
Protein: p.Lys625Arg
Coding: c.1874A>G
MANE Select: NM_001794
dbSNP: rs6142884
Type: single nucleotide variant
Location: chr20:61928292 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02
Residue 625: the cadherin 5 domain; a UniProt-annotated variant site (in)

Full CDH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDH4-related disorder

Similar variants

CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same condition
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same condition
CDH4 c.169+234620C>T Uncertain significance ★ same condition
CDH4 p.Ile738Leu Uncertain significance ★ ⚠ same condition
CDH4 c.1188+7C>A Likely benign same condition
CDH4 c.1189-9A>G Likely benign same condition
CDH4 c.170-244074G>T Likely benign same condition
CDH4 c.170-244081C>T 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/cdh4-p-lys625arg (accessed [today's date]).

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