Is REN p.Arg399His (c.1196G>A) pathogenic?

REN p.Arg399His (c.1196G>A) is classified Uncertain significance in REN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-19). AlphaMissense: likely benign (0.2301); Very rare (popmax 0.00322%, nfe); Associated with Inborn genetic diseases.

What condition is associated with REN p.Arg399His (c.1196G>A)?

REN p.Arg399His (c.1196G>A) is associated with Inborn genetic diseases (ClinVar).

How common is REN p.Arg399His (c.1196G>A) in the general population?

REN p.Arg399His (c.1196G>A) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about REN p.Arg399His (c.1196G>A)?

AlphaMissense predicts likely benign (score 0.2301) — an in-silico prediction, not a clinical call.

REN p.Arg399His

c.1196G>A · rs145852603 · VCV1503882

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2301	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -10.06	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 7.7	GERP 2.2, phastCons 1
Overall
CADD	28.5	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

Grpmax group 0.00322% European (non-Finnish) · 38/1,180,050 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00254% 41/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,054
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,924

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.Arg399His
Coding: c.1196G>A
MANE Select: NM_001363642 · reported on NM_000537
dbSNP: rs145852603
Type: single nucleotide variant
Location: chr1:204155041 (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.Lys139Ter Pathogenic ★★ same condition
REN p.Arg119His 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
REN p.Gly175Val Uncertain significance ★★ ⚠ same condition
REN p.Thr169Met 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-arg399his (accessed [today's date]).

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