Is REN p.Leu145Phe (c.433C>T) pathogenic?

REN p.Leu145Phe (c.433C>T) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.1059); Absent from gnomAD v4.1.

How common is REN p.Leu145Phe (c.433C>T) in the general population?

REN p.Leu145Phe (c.433C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REN p.Leu145Phe (c.433C>T)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

REN p.Leu145Phe

c.433C>T · VCV3680195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -0.77	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 2.2	GERP -1.2, phastCons 0.7
Overall
CADD	8.372	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: REN
Protein: p.Leu145Phe
Coding: c.433C>T
MANE Select: NM_001363642 · reported on NM_000537
Type: single nucleotide variant
Location: chr1:204160619 (GRCh38)
Structure: AlphaFold pLDDT 85.00

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

Similar variants

REN c.249+1G>A Pathogenic/Likely pathogenic ★★ same type
REN p.Arg49Ter Pathogenic/Likely pathogenic ★★ same type
REN p.Lys139Ter Pathogenic ★★ same type
REN p.Ala182Thr Uncertain significance ★★ ⚠ same type
REN p.Arg119Cys Uncertain significance ★★ ⚠ same type
REN p.Arg119His Uncertain significance ★★ ⚠ same type
REN p.Arg148His Uncertain significance ★★ ⚠ same type
REN p.Arg387Gln Uncertain significance ★★ ⚠ 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/ren-p-leu145phe (accessed [today's date]).

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