Is PRDM12 p.Arg147Cys (c.439C>T) pathogenic?

PRDM12 p.Arg147Cys (c.439C>T) is classified Uncertain significance in PRDM12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-03). AlphaMissense: ambiguous (0.4808); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with PRDM12 p.Arg147Cys (c.439C>T)?

PRDM12 p.Arg147Cys (c.439C>T) is associated with Inborn genetic diseases, congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

How common is PRDM12 p.Arg147Cys (c.439C>T) in the general population?

PRDM12 p.Arg147Cys (c.439C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about PRDM12 p.Arg147Cys (c.439C>T)?

AlphaMissense predicts ambiguous (score 0.4808) — an in-silico prediction, not a clinical call.

PRDM12 p.Arg147Cys

c.439C>T · rs965981905 · VCV2071798

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4808	ambiguous
REVEL	0.512	indeterminate
SaProt	LLR -10.39	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0075 · regional, not allelic
Overall
CADD	33.0	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00167% 27/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
East Asian	0.00891%	11,220
European (non-Finnish)	0.00169%	59,002
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: PRDM12
Protein: p.Arg147Cys
Coding: c.439C>T
MANE Select: NM_021619
dbSNP: rs965981905
Type: single nucleotide variant
Location: chr9:130668182 (GRCh38)
Gene constraint: LOEUF 1.153 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81 · 1 PDB
Residue 147: the set domain; a β-strand

Full PRDM12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital insensitivity to pain-hypohidrosis syndrome

Similar variants

PRDM12 p.Arg147His Uncertain significance ★★ ⚠ same residue
PRDM12 p.Ala332Val Uncertain significance ★★ ⚠ same condition
PRDM12 p.Arg158Trp Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn134Ser Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn141Ser Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn207Ser Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn277Lys Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn43Asp Uncertain significance ★★ ⚠ same condition

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/prdm12-p-arg147cys (accessed [today's date]).

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