Is CDH8 p.Pro394Leu (c.1181C>T) pathogenic?

CDH8 p.Pro394Leu (c.1181C>T) is classified Uncertain significance in CDH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely benign (0.1366); Very rare (popmax 0.00267%, afr).

How common is CDH8 p.Pro394Leu (c.1181C>T) in the general population?

CDH8 p.Pro394Leu (c.1181C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CDH8 p.Pro394Leu (c.1181C>T)?

AlphaMissense predicts likely benign (score 0.1366) — an in-silico prediction, not a clinical call.

CDH8 p.Pro394Leu

c.1181C>T · VCV3489024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1366	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 232 kb · p 1e-16 · regional, not allelic
Overall
CADD	26.0	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 0.00267% African / African-American · 2/74,842 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,613,766 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-Americangrpmax	0.00267%	37,421
European (non-Finnish)	0.00136%	73,746
South Asian	0.0011%	91,076

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: CDH8
Protein: p.Pro394Leu
Coding: c.1181C>T
MANE Select: NM_001796
Type: single nucleotide variant
Location: chr16:61817575 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.26
Residue 394: the cadherin 4 domain

Full CDH8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH8 p.Arg666Cys Likely benign ★★ same type
CDH8 p.Ile429= Benign ★★ same type
CDH8 p.Tyr667= Benign/Likely benign ★★ same type
CDH8 p.Ala30Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala332Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala443Thr Uncertain significance ★ ⚠ same type
CDH8 p.Ala502Gly Uncertain significance ★ ⚠ same type
CDH8 p.Ala629Val 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/cdh8-p-pro394leu (accessed [today's date]).

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