Is CDH20 p.Glu148Lys (c.442G>A) pathogenic?

CDH20 p.Glu148Lys (c.442G>A) is classified Uncertain significance in CDH20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely pathogenic (0.6603); Ultra-rare (popmax 0.0167%, amr).

How common is CDH20 p.Glu148Lys (c.442G>A) in the general population?

CDH20 p.Glu148Lys (c.442G>A) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CDH20 p.Glu148Lys (c.442G>A)?

AlphaMissense predicts likely pathogenic (score 0.6603) — an in-silico prediction, not a clinical call.

CDH20 p.Glu148Lys

c.442G>A · VCV3488873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6603	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -11.18	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 60 kb · p 2.3e-07 · regional, not allelic
Overall
CADD	27.5	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 0.0167% Admixed American · 10/59,992 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00285% 46/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.63%	38
Admixed Americangrpmax	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.0022%	45,534
African / African-American	0.00133%	74,934
European (non-Finnish)	0.000508%	196,668

Amish 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: CDH20
Protein: p.Glu148Lys
Coding: c.442G>A
MANE Select: NM_031891
Type: single nucleotide variant
Location: chr18:61499381 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 148: the cadherin 1 domain

Full CDH20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH20 p.Arg687Trp Uncertain significance ★★ ⚠ same type
CDH20 p.Pro39= Benign ★★ same type
CDH20 p.Ala226Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala403Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala506Thr Uncertain significance ★ ⚠ same type
CDH20 p.Ala610Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala627Thr Uncertain significance ★ ⚠ same type
CDH20 p.Ala691Thr 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/cdh20-p-glu148lys (accessed [today's date]).

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