Is REN p.Met53Val (c.157A>G) pathogenic?

REN p.Met53Val (c.157A>G) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0584); Very rare (popmax 8.47e-05%, nfe).

How common is REN p.Met53Val (c.157A>G) in the general population?

REN p.Met53Val (c.157A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about REN p.Met53Val (c.157A>G)?

AlphaMissense predicts likely benign (score 0.0584) — an in-silico prediction, not a clinical call.

REN p.Met53Val

c.157A>G · rs2527493841 · VCV1970371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0584	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -4.77	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 -0.078	GERP -3.2
Overall
CADD	3.812	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.2e-05% 1/1,614,132 alleles · very rare exomes 1/1,461,874 · genomes 0/152,258 · 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: REN
Protein: p.Met53Val
Coding: c.157A>G
MANE Select: NM_000537
dbSNP: rs2527493841
Type: single nucleotide variant
Location: chr1:204162105 (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-met53val (accessed [today's date]).

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