Is PRR12 p.Pro321Ser (c.961C>T) pathogenic?

PRR12 p.Pro321Ser (c.961C>T) is classified Conflicting classifications of pathogenicity in PRR12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-24). AlphaMissense: likely benign (0.0761); Ultra-rare (popmax 0.026%, afr); Associated with Inborn genetic diseases.

What condition is associated with PRR12 p.Pro321Ser (c.961C>T)?

PRR12 p.Pro321Ser (c.961C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRR12 p.Pro321Ser (c.961C>T) in the general population?

PRR12 p.Pro321Ser (c.961C>T) is ultra-rare (popmax 0.026%, afr) (gnomAD).

What do computational predictors say about PRR12 p.Pro321Ser (c.961C>T)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

PRR12 p.Pro321Ser

c.961C>T · VCV3938602

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.63	GERP 1.5, phastCons 0.11
Regional constraint	o/e 1.05	unconstrained · MANE · 1,070 bp · p 0.23 · regional, not allelic
Overall
CADD	15.91	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 0.026% African / African-American · 19/73,074 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.00589% 91/1,545,512 alleles · ultra-rare exomes 71/1,393,234 · genomes 20/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.026%	3,846
Finnishnot grpmax-eligible	0.0141%	7,069
Remaining individualsnot grpmax-eligible	0.01%	9,976
European (non-Finnish)	0.0048%	20,843
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,570
South Asian	0.00238%	41,935

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: PRR12
Protein: p.Pro321Ser
Coding: c.961C>T
MANE Select: NM_020719
Type: single nucleotide variant
Location: chr19:49595296 (GRCh38)
Gene constraint: LOEUF 0.18 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 43.84
Residue 321: a UniProt-annotated variant site (in noc1)

Full PRR12 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

Similar variants

PRR12 p.Pro321His Uncertain significance ★★ ⚠ same residue
PRR12 p.Ala1190Ser Uncertain significance ★★ ⚠ same condition
PRR12 p.Ala82Gly Uncertain significance ★★ ⚠ same condition
PRR12 p.Arg1755Gln Uncertain significance ★★ ⚠ same condition
PRR12 p.Asp1109Tyr Uncertain significance ★★ ⚠ same condition
PRR12 p.Glu1100Lys Uncertain significance ★★ ⚠ same condition
PRR12 p.Glu943Ala Uncertain significance ★★ ⚠ same condition
PRR12 p.Gly1566Ser 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/prr12-p-pro321ser (accessed [today's date]).

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