Is CDH4 p.Ala33Thr (c.97G>A) pathogenic?

CDH4 p.Ala33Thr (c.97G>A) is classified Benign in CDH4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0795); Low-frequency (popmax 2.58%, afr).

How common is CDH4 p.Ala33Thr (c.97G>A) in the general population?

CDH4 p.Ala33Thr (c.97G>A) is low-frequency (popmax 2.58%, afr) (gnomAD).

What do computational predictors say about CDH4 p.Ala33Thr (c.97G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

CDH4 p.Ala33Thr

c.97G>A · rs144744391 · VCV769098

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.58%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -5.40	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 3.4	GERP -0.28, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 521 kb · p 0.43 · regional, not allelic
Overall
CADD	17.39	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 2.58% African / African-American · 1,935/74,996 alleles

Filtering AF 2.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.45%

Overall 0.136% 2,190/1,612,986 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.58%	39
Admixed American	0.167%	600
Remaining individualsnot grpmax-eligible	0.162%	618
Middle Eastern	0.066%	1,516
South Asian	0.00769%	13,008
European (non-Finnish)	0.00365%	27,418

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: CDH4
Protein: p.Ala33Thr
Coding: c.97G>A
MANE Select: NM_001794
dbSNP: rs144744391
Type: single nucleotide variant
Location: chr20:61254865 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 79.02

Full CDH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH4 p.Thr396Met Uncertain significance ★★ ⚠ same type
CDH4 p.Val580Ile Uncertain significance ★★ ⚠ same type
CDH4 c.1629-8C>T Benign ★★ same type
CDH4 c.2240-4A>G Benign ★★ same type
CDH4 p.Ala344= Benign/Likely benign ★★ same type
CDH4 p.Asn283= Benign/Likely benign ★★ same type
CDH4 p.Asn450= Benign/Likely benign ★★ same type
CDH4 p.Ile691= Benign ★★ 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/cdh4-p-ala33thr (accessed [today's date]).

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