Is PRDM12 p.Pro216= (c.648C>T) pathogenic?

PRDM12 p.Pro216= (c.648C>T) is classified Benign in PRDM12 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 46.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital insensitivity to pain-hypohidrosis syndrome.

What condition is associated with PRDM12 p.Pro216= (c.648C>T)?

PRDM12 p.Pro216= (c.648C>T) is associated with congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

PRDM12 p.Pro216=

Q: How common is PRDM12 p.Pro216= (c.648C>T) in the general population?

PRDM12 p.Pro216= (c.648C>T) is common (popmax 46.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Hereditary sensory and autonomic neuropathy type 8 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.648C>T · rs7021384 · VCV1165169

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 46.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

congenital insensitivity to pain-hypohidrosis syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -4.8
Overall
CADD	0.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 46.7% East Asian · 20,871/44,656 alleles

Filtering AF 46.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 46%

Overall 32.7% 526,423/1,611,544 alleles · common exomes 474,192/1,459,724 · genomes 52,231/151,820 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	46.7%	2
Admixed American	43.5%	2
South Asian	35.4%	3
Middle Eastern	35.3%	3
African / African-American	35.1%	3
Remaining individualsnot grpmax-eligible	33.8%	3
Finnishnot grpmax-eligible	33.7%	3
Ashkenazi Jewishnot grpmax-eligible	33.6%	3
Amishnot grpmax-eligible	31.4%	3
European (non-Finnish)	31.1%	3

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.Pro216=
Coding: c.648C>T
MANE Select: NM_021619
dbSNP: rs7021384
Type: single nucleotide variant
Location: chr9:130678606 (GRCh38)
Gene constraint: LOEUF 1.153 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81 · 1 PDB

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

Disease context

congenital insensitivity to pain-hypohidrosis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PRDM12 p.Ala332Val Uncertain significance ★★ ⚠ same condition
PRDM12 p.Arg147Cys Uncertain significance ★★ same condition
PRDM12 p.Arg147His 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

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-pro216 (accessed [today's date]).

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