Is CDH3 p.Pro548Ser (c.1642C>T) pathogenic?

CDH3 p.Pro548Ser (c.1642C>T) is classified Uncertain significance in CDH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-02). AlphaMissense: ambiguous (0.4497); Very rare (popmax 0.00223%, eas).

How common is CDH3 p.Pro548Ser (c.1642C>T) in the general population?

CDH3 p.Pro548Ser (c.1642C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDH3 p.Pro548Ser (c.1642C>T)?

AlphaMissense predicts ambiguous (score 0.4497) — an in-silico prediction, not a clinical call.

CDH3 p.Pro548Ser

c.1642C>T · rs749323804 · VCV1435729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4497	ambiguous
REVEL	0.212	benign-leaning
SaProt	LLR -9.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 53 kb · p 0.35 · regional, not allelic
Overall
CADD	24.7	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00136% 22/1,614,038 alleles · very rare exomes 18/1,461,856 · genomes 4/152,182 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asiangrpmax	0.00223%	44,888
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00153%	65,557

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDH3
Protein: p.Pro548Ser
Coding: c.1642C>T
MANE Select: NM_001793
dbSNP: rs749323804
Type: single nucleotide variant
Location: chr16:68687583 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.71 · 19 PDB
Residue 548: the cadherin 5 domain

Full CDH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CDH3 p.Arg221Ter Pathogenic ★★ same type
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same type
CDH3 p.Gln299Ter Pathogenic ★★ same type
CDH3 p.Glu708Ter Likely pathogenic ★★ same type
CDH3 p.Trp362Ter Pathogenic ★★ 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/cdh3-p-pro548ser (accessed [today's date]).

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