Is CDH1 p.Ser70Pro (c.208T>C) pathogenic?

CDH1 p.Ser70Pro (c.208T>C) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-10). AlphaMissense: ambiguous (0.3889); Very rare (popmax 0.004%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ser70Pro (c.208T>C)?

CDH1 p.Ser70Pro (c.208T>C) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, hereditary breast carcinoma (ClinVar).

How common is CDH1 p.Ser70Pro (c.208T>C) in the general population?

CDH1 p.Ser70Pro (c.208T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CDH1 p.Ser70Pro (c.208T>C)?

AlphaMissense predicts ambiguous (score 0.3889) — an in-silico prediction, not a clinical call.

CDH1 p.Ser70Pro

c.208T>C · rs587781862 · VCV141592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3889	ambiguous
REVEL	0.318	indeterminate
SaProt	LLR -9.83	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 2.5, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic
Overall
CADD	12.95	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 0.004% African / African-American · 3/74,908 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,046 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,969
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ser70Pro
Coding: c.208T>C
MANE Select: NM_004360
dbSNP: rs587781862
Type: single nucleotide variant
Location: chr16:68801714 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary diffuse gastric adenocarcinoma hereditary breast carcinoma

Similar variants

CDH1 p.Ser70Thr Uncertain significance ★★ ⚠ same residue
CDH1 p.Ser70Tyr Uncertain significance ★ ⚠ same residue
CDH1 p.Ser70= Benign ★ same residue
CDH1 p.Ser70fs Pathogenic ★★★ 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
CDH1 c.1320+1G>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-ser70pro (accessed [today's date]).

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