Is CDH17 p.Arg74Trp (c.220C>T) pathogenic?

CDH17 p.Arg74Trp (c.220C>T) is classified Uncertain significance in CDH17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely benign (0.1498); Ultra-rare (popmax 0.0538%, sas).

How common is CDH17 p.Arg74Trp (c.220C>T) in the general population?

CDH17 p.Arg74Trp (c.220C>T) is ultra-rare (popmax 0.0538%, sas) (gnomAD).

What do computational predictors say about CDH17 p.Arg74Trp (c.220C>T)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

CDH17 p.Arg74Trp

c.220C>T · rs569997084 · VCV2336204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0538%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -9.48	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 -1.3	GERP -1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 66 kb · p 0.44 · regional, not allelic
Overall
CADD	18.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0538% South Asian · 49/91,062 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0375%

Overall 0.00576% 93/1,613,460 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0538%	1,858
East Asian	0.00892%	11,211
Admixed American	0.00834%	11,998
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.00246%	40,673
Finnishnot grpmax-eligible	0.00156%	64,016

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: CDH17
Protein: p.Arg74Trp
Coding: c.220C>T
MANE Select: NM_004063
dbSNP: rs569997084
Type: single nucleotide variant
Location: chr8:94177652 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.98 · 3 PDB
Residue 74: the cadherin 1 domain

Full CDH17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH17 p.Leu362Arg Uncertain significance ★★ ⚠ same type
CDH17 p.Ala788= Benign/Likely benign ★★ same type
CDH17 p.Arg499His Benign ★★ same type
CDH17 p.Glu739Ala Benign ★★ ⚠ same type
CDH17 c.1796+2T>C Uncertain significance ★ same type
CDH17 p.Ala101Ser Uncertain significance ★ ⚠ same type
CDH17 p.Ala157Thr Uncertain significance ★ ⚠ same type
CDH17 p.Ala241Ser Uncertain significance ★ ⚠ same type

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/cdh17-p-arg74trp (accessed [today's date]).

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