Is REN p.Pro374Leu (c.1121C>T) pathogenic?

REN p.Pro374Leu (c.1121C>T) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.2735); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with REN p.Pro374Leu (c.1121C>T)?

REN p.Pro374Leu (c.1121C>T) is associated with Inborn genetic diseases (ClinVar).

How common is REN p.Pro374Leu (c.1121C>T) in the general population?

REN p.Pro374Leu (c.1121C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about REN p.Pro374Leu (c.1121C>T)?

AlphaMissense predicts likely benign (score 0.2735) — an in-silico prediction, not a clinical call.

REN p.Pro374Leu

c.1121C>T · VCV3944524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2735 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2735	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -11.73	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.1, phastCons 1
Overall
CADD	26.9	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

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.Pro374Leu
Coding: c.1121C>T
MANE Select: NM_000537
Type: single nucleotide variant
Location: chr1:204155116 (GRCh38)
Structure: AlphaFold pLDDT 85.00

Full REN 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

Similar variants

REN p.Pro374Ser Uncertain significance ★ ⚠ same residue
REN p.Lys139Ter Pathogenic ★★ same condition
REN p.Arg119His Uncertain significance ★★ ⚠ same condition
REN p.Arg399His Uncertain significance ★★ ⚠ same condition
REN p.Gln160Arg Uncertain significance ★★ ⚠ same condition
REN p.Glu253Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu310Lys Uncertain significance ★★ ⚠ same condition
REN p.Glu89Lys 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/ren-p-pro374leu (accessed [today's date]).

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