Is PCDH12 p.Arg464Ser (c.1392G>T) pathogenic?

PCDH12 p.Arg464Ser (c.1392G>T) is classified Uncertain significance in PCDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely benign (0.2059); Very rare (popmax 0.000932%, nfe).

How common is PCDH12 p.Arg464Ser (c.1392G>T) in the general population?

PCDH12 p.Arg464Ser (c.1392G>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about PCDH12 p.Arg464Ser (c.1392G>T)?

AlphaMissense predicts likely benign (score 0.2059) — an in-silico prediction, not a clinical call.

PCDH12 p.Arg464Ser

c.1392G>T · rs759589459 · VCV1477687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2059	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -3.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -1.5, phastCons 0.55
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.0016 · regional, not allelic
Overall
CADD	14.61	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 0.000932% European (non-Finnish) · 11/1,180,022 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000681% 11/1,614,196 alleles · very rare exomes 11/1,461,894 · genomes 0/152,302 · joint denominator

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: PCDH12
Protein: p.Arg464Ser
Coding: c.1392G>T
MANE Select: NM_016580
dbSNP: rs759589459
Type: single nucleotide variant
Location: chr5:141956460 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.22
Residue 464: the cadherin 5 domain

Full PCDH12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCDH12 p.Arg151Ter Pathogenic ★★ same type
PCDH12 p.Arg308Ter Pathogenic/Likely pathogenic ★★ same type
PCDH12 p.Arg839Ter Pathogenic ★★ same type
PCDH12 p.Ala1132Thr Uncertain significance ★★ ⚠ same type
PCDH12 p.Ala148Thr Uncertain significance ★★ ⚠ same type
PCDH12 p.Ala802Val Uncertain significance ★★ ⚠ same type
PCDH12 p.Ala905Thr Uncertain significance ★★ ⚠ same type
PCDH12 p.Arg1049Gln 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/pcdh12-p-arg464ser (accessed [today's date]).

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