Is REN p.Val76Met (c.226G>A) pathogenic?

REN p.Val76Met (c.226G>A) is classified Uncertain significance in REN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely benign (0.1545); Very rare (popmax 0.00769%, sas).

How common is REN p.Val76Met (c.226G>A) in the general population?

REN p.Val76Met (c.226G>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about REN p.Val76Met (c.226G>A)?

AlphaMissense predicts likely benign (score 0.1545) — an in-silico prediction, not a clinical call.

REN p.Val76Met

c.226G>A · VCV4797064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1545	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -8.15	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 1.5	GERP 1.3, phastCons 0.053
Overall
CADD	19.9	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 0.00769% South Asian · 7/91,068 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00123% 18/1,461,858 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,010
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,880
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	0.000593%	168,576

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.Val76Met
Coding: c.226G>A
MANE Select: NM_001363642 · reported on NM_000537
Type: single nucleotide variant
Location: chr1:204162036 (GRCh38)
Structure: AlphaFold pLDDT 85.00

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

Similar variants

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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-val76met (accessed [today's date]).

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