Is CDH1 p.Ser850Phe (c.2549C>T) pathogenic?

CDH1 p.Ser850Phe (c.2549C>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.6308); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ser850Phe (c.2549C>T)?

CDH1 p.Ser850Phe (c.2549C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Ser850Phe (c.2549C>T) in the general population?

CDH1 p.Ser850Phe (c.2549C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Ser850Phe (c.2549C>T)?

AlphaMissense predicts likely pathogenic (score 0.6308) — an in-silico prediction, not a clinical call.

CDH1 p.Ser850Phe

c.2549C>T · rs1337211551 · VCV857593

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6308 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6308	likely pathogenic
REVEL	0.568	indeterminate
SaProt	LLR -11.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Ser850Phe
Coding: c.2549C>T
MANE Select: NM_004360
dbSNP: rs1337211551
Type: single nucleotide variant
Location: chr16:68833399 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 850: the 'required for binding alpha, beta and gamma catenins' region

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

Similar variants

CDH1 p.Ser850Cys Uncertain significance ★★ same residue
CDH1 p.Ser850Pro Uncertain significance ★★ ⚠ same residue
CDH1 p.Ser850Tyr Uncertain significance ★★ ⚠ same residue
CDH1 p.Ser850= Benign/Likely benign ★★ same residue
CDH1 p.Ser850fs Uncertain significance ★★★ same residue
CDH1 p.Ser850Leu Uncertain significance ★★ same residue
CDH1 p.Ser850Ala Uncertain significance ★ ⚠ same residue
CDH1 c.1008+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-ser850phe (accessed [today's date]).

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