Is PREPL p.Phe273Ser (c.818T>C) pathogenic?

PREPL p.Phe273Ser (c.818T>C) is classified Uncertain significance in PREPL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-13). AlphaMissense: likely pathogenic (0.77); Very rare (popmax 0.00364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PREPL p.Phe273Ser (c.818T>C)?

PREPL p.Phe273Ser (c.818T>C) is associated with Inborn genetic diseases, myasthenic syndrome, congenital, 22 (ClinVar).

How common is PREPL p.Phe273Ser (c.818T>C) in the general population?

PREPL p.Phe273Ser (c.818T>C) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about PREPL p.Phe273Ser (c.818T>C)?

AlphaMissense predicts likely pathogenic (score 0.77) — an in-silico prediction, not a clinical call.

PREPL p.Phe273Ser

c.818T>C · rs1347512792 · VCV1050574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.77 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.77	likely pathogenic
REVEL	0.23	benign-leaning
SaProt	LLR -8.81	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 11	GERP 2.5, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F362S vs ClinVar F273S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00364% European (non-Finnish) · 43/1,179,878 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00304% 49/1,613,584 alleles · very rare exomes 47/1,461,356 · genomes 2/152,228 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00961%	10,411
European (non-Finnish)grpmax	0.00364%	27,439

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PREPL
Protein: p.Phe273Ser
Coding: c.818T>C
MANE Select: NM_001171613
dbSNP: rs1347512792
Type: single nucleotide variant
Location: chr2:44338421 (GRCh38)
Gene constraint: LOEUF 1.247 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 2 PDB
Residue 362 UniProt numbering: a β-strand

Full PREPL 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: myasthenic syndrome, congenital, 22

Similar variants

PREPL p.Phe273Leu Uncertain significance ★ ⚠ same residue
PREPL c.1262+1G>A Pathogenic/Likely pathogenic ★★ same condition
PREPL c.1263-1G>C Pathogenic/Likely pathogenic ★★ same condition
PREPL c.-49+1734C>T Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Gln14Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Gln456Ter Pathogenic/Likely pathogenic ★★ same condition
PREPL p.Glu577Ter Pathogenic ★★ 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/prepl-p-phe273ser (accessed [today's date]).

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