Is CDH4 p.Ala852Thr (c.2554G>A) pathogenic?

CDH4 p.Ala852Thr (c.2554G>A) is classified Uncertain significance in CDH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-01). AlphaMissense: likely benign (0.2731); Very rare (popmax 0.00903%, nfe); Associated with Simplified gyral pattern.

What condition is associated with CDH4 p.Ala852Thr (c.2554G>A)?

CDH4 p.Ala852Thr (c.2554G>A) is associated with Simplified gyral pattern (ClinVar).

How common is CDH4 p.Ala852Thr (c.2554G>A) in the general population?

CDH4 p.Ala852Thr (c.2554G>A) is very rare (popmax 0.00903%, nfe) (gnomAD).

What do computational predictors say about CDH4 p.Ala852Thr (c.2554G>A)?

AlphaMissense predicts likely benign (score 0.2731) — an in-silico prediction, not a clinical call.

CDH4 p.Ala852Thr

c.2554G>A · rs373341715 · VCV438597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00903%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Simplified gyral pattern

Computational evidence

Protein change
AlphaMissense	0.2731	likely benign
REVEL	0.522	indeterminate
SaProt	LLR -6.87	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 12	GERP 1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,823 bp · p 0.76 · regional, not allelic
Overall
CADD	25.7	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 0.00903% European (non-Finnish) · 106/1,173,656 alleles

Filtering AF 0.00761% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0071%

Overall 0.0077% 123/1,598,232 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0129%	7,737
European (non-Finnish)grpmax	0.00903%	11,072
Finnishnot grpmax-eligible	0.00638%	15,670
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,002
Admixed American	0.00344%	29,049
African / African-American	0.0027%	37,006

Remaining individuals 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: CDH4
Protein: p.Ala852Thr
Coding: c.2554G>A
MANE Select: NM_001794
dbSNP: rs373341715
Type: single nucleotide variant
Location: chr20:61936746 (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

Disease context

Simplified gyral pattern — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH4 p.Glu451Lys Uncertain significance ★ ⚠ same condition
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.Ala33Thr Benign ★★ same type
CDH4 p.Ala344= Benign/Likely benign ★★ same type
CDH4 p.Asn283= Benign/Likely 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-ala852thr (accessed [today's date]).

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