Is PRIMA1 p.Pro84Ala (c.250C>G) pathogenic?

PRIMA1 p.Pro84Ala (c.250C>G) is classified Uncertain significance in PRIMA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-09). AlphaMissense: likely benign (0.1165); Very rare (popmax 0.00102%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with PRIMA1 p.Pro84Ala (c.250C>G)?

PRIMA1 p.Pro84Ala (c.250C>G) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is PRIMA1 p.Pro84Ala (c.250C>G) in the general population?

PRIMA1 p.Pro84Ala (c.250C>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

What do computational predictors say about PRIMA1 p.Pro84Ala (c.250C>G)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

PRIMA1 p.Pro84Ala

c.250C>G · rs376511394 · VCV1392225

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -7.30	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.9 · regional, not allelic
Overall
CADD	25.9	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 0.00102% European (non-Finnish) · 12/1,179,998 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,110 alleles · very rare exomes 12/1,461,780 · genomes 0/152,330 · 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: PRIMA1
Protein: p.Pro84Ala
Coding: c.250C>G
MANE Select: NM_178013
dbSNP: rs376511394
Type: single nucleotide variant
Location: chr14:93737350 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 63.74 · 1 PDB

Full PRIMA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PRIMA1 p.Pro84= Likely benign ★ same residue
PRIMA1 p.Arg55Trp Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Asn79Ser Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Gly145Arg Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Ile118Thr Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Leu6Val Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Pro59Leu Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Ser103Phe 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/prima1-p-pro84ala (accessed [today's date]).

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