Is CDH12 p.Ser374Arg (c.1122C>G) pathogenic?

CDH12 p.Ser374Arg (c.1122C>G) is classified Uncertain significance in CDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.6483); Very rare (popmax 0.00133%, afr).

How common is CDH12 p.Ser374Arg (c.1122C>G) in the general population?

CDH12 p.Ser374Arg (c.1122C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CDH12 p.Ser374Arg (c.1122C>G)?

AlphaMissense predicts likely pathogenic (score 0.6483) — an in-silico prediction, not a clinical call.

CDH12 p.Ser374Arg

c.1122C>G · rs2477925959 · VCV3141083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6483	likely pathogenic
REVEL	0.146	moderately benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -1.8
Regional constraint	o/e 1.00	unconstrained · MANE · 223 kb · p 0.95 · regional, not allelic
Overall
CADD	12.29	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 0.00133% African / African-American · 1/74,988 alleles

Overall 6.84e-05% 1/1,461,708 alleles · very rare

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: CDH12
Protein: p.Ser374Arg
Coding: c.1122C>G
MANE Select: NM_004061
dbSNP: rs2477925959
Type: single nucleotide variant
Location: chr5:21802301 (GRCh38)
Gene constraint: LOEUF 0.668 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 374: the cadherin 3 domain

Full CDH12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH12 c.1003-3C>T Benign ★★ same type
CDH12 p.Asp780= Likely benign ★★ same type
CDH12 p.Gln60= Benign ★★ same type
CDH12 p.Glu349Asp Benign ★★ ⚠ same type
CDH12 p.Glu34Gln Benign ★★ same type
CDH12 p.Ile475Thr Benign ★★ ⚠ same type
CDH12 p.Ile598= Likely benign ★★ same type
CDH12 p.Pro213= 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/cdh12-p-ser374arg (accessed [today's date]).

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