Is PRIMA1 p.Pro122Ser (c.364C>T) pathogenic?

PRIMA1 p.Pro122Ser (c.364C>T) is classified Uncertain significance in PRIMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.8355); Very rare (popmax 0.00399%, nfe); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with PRIMA1 p.Pro122Ser (c.364C>T)?

PRIMA1 p.Pro122Ser (c.364C>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is PRIMA1 p.Pro122Ser (c.364C>T) in the general population?

PRIMA1 p.Pro122Ser (c.364C>T) is very rare (popmax 0.00399%, 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.Pro122Ser (c.364C>T)?

AlphaMissense predicts likely pathogenic (score 0.8355) — an in-silico prediction, not a clinical call.

PRIMA1 p.Pro122Ser

c.364C>T · rs1434626074 · VCV845343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.8355	likely pathogenic · top 7% in PRIMA1
REVEL	0.21	benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 66 kb · p 0.9 · regional, not allelic
Overall
CADD	27.0	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 0.00399% European (non-Finnish) · 47/1,178,066 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00298% 48/1,611,482 alleles · very rare exomes 47/1,459,370 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,065
African / African-American	0.00134%	74,876

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.Pro122Ser
Coding: c.364C>T
MANE Select: NM_178013
dbSNP: rs1434626074
Type: single nucleotide variant
Location: chr14:93721542 (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.Pro122Leu Uncertain significance ★ ⚠ same residue
PRIMA1 p.Pro122= 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

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-pro122ser (accessed [today's date]).

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