Is PREPL p.Phe616Leu (c.1848C>G) pathogenic?

PREPL p.Phe616Leu (c.1848C>G) is classified Uncertain significance in PREPL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.9856); Very rare (popmax 0.00989%, sas).

How common is PREPL p.Phe616Leu (c.1848C>G) in the general population?

PREPL p.Phe616Leu (c.1848C>G) is very rare (popmax 0.00989%, sas) (gnomAD).

What do computational predictors say about PREPL p.Phe616Leu (c.1848C>G)?

AlphaMissense predicts likely pathogenic (score 0.9856) — an in-silico prediction, not a clinical call.

PREPL p.Phe616Leu

c.1848C>G · VCV3906752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00989%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9856	likely pathogenic · top 1% in PREPL
REVEL	0.372	indeterminate
SaProt	LLR -10.44	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 25 kb · p 1e-15 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F705L vs ClinVar F616L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00989% South Asian · 9/90,986 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000558% 9/1,612,640 alleles · very rare exomes 9/1,460,566 · genomes 0/152,074 · 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: PREPL
Protein: p.Phe616Leu
Coding: c.1848C>G
MANE Select: NM_001171613
Type: single nucleotide variant
Location: chr2:44321425 (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 705 UniProt numbering: a UniProt-annotated variant site (found in a patient with intellectual disability, short stature, chronic lung disease and failure to thrive; uncertain significance); an α-helix

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

Similar variants

SLC3A1 p.Ala616Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PREPL p.Phe616= Likely benign ★ same residue
PREPL c.1262+1G>A Pathogenic/Likely pathogenic ★★ same type
PREPL c.1263-1G>C Pathogenic/Likely pathogenic ★★ same type
PREPL c.-49+1734C>T Pathogenic/Likely pathogenic ★★ same type
PREPL p.Arg206Ter Pathogenic/Likely pathogenic ★★ same type
PREPL p.Gln14Ter Pathogenic/Likely pathogenic ★★ same type
PREPL p.Gln456Ter Pathogenic/Likely pathogenic ★★ same type

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-phe616leu (accessed [today's date]).

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