Is CDH16 p.Arg185Trp (c.553C>T) pathogenic?

CDH16 p.Arg185Trp (c.553C>T) is classified Uncertain significance in CDH16 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0843); Ultra-rare (popmax 0.0396%, sas).

How common is CDH16 p.Arg185Trp (c.553C>T) in the general population?

CDH16 p.Arg185Trp (c.553C>T) is ultra-rare (popmax 0.0396%, sas) (gnomAD).

What do computational predictors say about CDH16 p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

CDH16 p.Arg185Trp

c.553C>T · rs756419589 · VCV2409181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0396%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.34, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,670 bp · p 0.11 · regional, not allelic
Overall
CADD	25.1	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 0.0396% South Asian · 36/90,992 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00342% 50/1,460,744 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0396%	2,528
Middle Eastern	0.0173%	5,766
East Asian	0.0111%	8,970
Remaining individualsnot grpmax-eligible	0.0032%	31,220
European (non-Finnish)	0.000509%	196,635

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: CDH16
Protein: p.Arg185Trp
Coding: c.553C>T
MANE Select: NM_004062
dbSNP: rs756419589
Type: single nucleotide variant
Location: chr16:66915250 (GRCh38)
Gene constraint: LOEUF 1.079 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.17
Residue 185: the cadherin 2 domain

Full CDH16 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH16 p.Arg185Gln Likely benign ★ same residue
CDH16 p.Arg717His Benign ★★ same type
CDH16 p.Leu377= Benign ★★ same type
CDH16 p.Ala133Ser Uncertain significance ★ ⚠ same type
CDH16 p.Ala159Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala173Thr Uncertain significance ★ ⚠ same type
CDH16 p.Ala202Val Uncertain significance ★ ⚠ same type
CDH16 p.Ala20Thr 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/cdh16-p-arg185trp (accessed [today's date]).

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