Is CDH1 p.His632= (c.1896C>T) pathogenic?

CDH1 p.His632= (c.1896C>T) is classified Benign in CDH1 (ClinVar, Expert panel, 20 submitters; last evaluated 2023-08-10). Common (popmax 8.84%, mid) — too common for a highly-penetrant pathogenic allele; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.His632= (c.1896C>T)?

CDH1 p.His632= (c.1896C>T) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, breast cancer, hereditary diffuse gastric adenocarcinoma (ClinVar).

CDH1 p.His632=

Q: How common is CDH1 p.His632= (c.1896C>T) in the general population?

CDH1 p.His632= (c.1896C>T) is common (popmax 8.84%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1896C>T · rs33969373 · VCV141570

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 20 submitters

gnomAD v4.1

Common

common (popmax 8.84%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):

BP2 BA1

Curation rationale (ClinGen, verbatim)

The NM_004360.5(CDH1):c.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 -13	GERP -3.6
Overall
CADD	0.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.84% Middle Eastern · 536/6,062 alleles

Filtering AF 8.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.98%

Overall 0.921% 14,861/1,614,096 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	8.84%	11
African / African-American	5.1%	20
Amishnot grpmax-eligible	3.63%	28
Admixed American	1.6%	63
Remaining individualsnot grpmax-eligible	1.41%	71
Ashkenazi Jewishnot grpmax-eligible	0.899%	111
European (non-Finnish)	0.661%	151
Finnishnot grpmax-eligible	0.536%	187
South Asian	0.234%	428
East Asian	0.0111%	8,978

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: CDH1
Protein: p.His632=
Coding: c.1896C>T
MANE Select: NM_004360
dbSNP: rs33969373
Type: single nucleotide variant
Location: chr16:68822185 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 632: the cadherin 5 domain; a β-strand

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: breast cancer hereditary diffuse gastric adenocarcinoma prostate cancer hereditary neoplastic syndrome

Similar variants

CDH1 p.His632Leu Uncertain significance ★★ ⚠ same residue
CDH1 p.His632Tyr Uncertain significance ★★ ⚠ same residue
CDH1 p.His632Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.His632fs Pathogenic ★★★ same residue
CDH1 p.His632Gln Uncertain significance ★ ⚠ same residue
CDH1 c.1008+2T>C Likely pathogenic ★★★ same condition
CDH1 c.1137+1G>A Pathogenic ★★★ same condition
CDH1 c.1137+2T>C Likely pathogenic ★★★ 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/cdh1-p-his632 (accessed [today's date]).

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