Is CDH17 p.Val274Asp (c.821T>A) pathogenic?

CDH17 p.Val274Asp (c.821T>A) is classified Uncertain significance in CDH17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1085); Very rare (popmax 0.000424%, nfe).

How common is CDH17 p.Val274Asp (c.821T>A) in the general population?

CDH17 p.Val274Asp (c.821T>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CDH17 p.Val274Asp (c.821T>A)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

CDH17 p.Val274Asp

c.821T>A · VCV4223727

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -5.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.46	GERP -4.4
Regional constraint	o/e 0.98	unconstrained · MANE · 66 kb · p 0.44 · regional, not allelic
Overall
CADD	10.21	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 0.000424% European (non-Finnish) · 5/1,179,812 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,570 alleles · very rare

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.Val274Asp
Coding: c.821T>A
MANE Select: NM_004063
Type: single nucleotide variant
Location: chr8:94170948 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.98 · 3 PDB
Residue 274: a β-strand; the cadherin 3 domain

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

Similar variants

CDH17 p.Val274Ala Likely benign ★ same residue
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

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-val274asp (accessed [today's date]).

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