Is RNPEP p.Val397Met (c.1189G>A) pathogenic?

RNPEP p.Val397Met (c.1189G>A) is classified Uncertain significance in RNPEP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.7001); Very rare (popmax 0.00334%, amr).

How common is RNPEP p.Val397Met (c.1189G>A) in the general population?

RNPEP p.Val397Met (c.1189G>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about RNPEP p.Val397Met (c.1189G>A)?

AlphaMissense predicts likely pathogenic (score 0.7001) — an in-silico prediction, not a clinical call.

RNPEP p.Val397Met

c.1189G>A · VCV4579098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7001	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -10.38	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.025 · regional, not allelic
Overall
CADD	32.0	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 0.00334% Admixed American · 2/59,908 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.0013% 21/1,613,266 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,954
Remaining individualsnot grpmax-eligible	0.0032%	31,232
East Asian	0.00223%	44,890
South Asian	0.0022%	45,447
African / African-American	0.00134%	74,900
European (non-Finnish)	0.0011%	90,741

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: RNPEP
Protein: p.Val397Met
Coding: c.1189G>A
MANE Select: NM_020216
Type: single nucleotide variant
Location: chr1:202000000 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.04

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

Similar variants

RNPEP p.Arg317Cys Benign ★★ ⚠ same type
RNPEP p.Thr184= Benign ★★ same type
RNPEP p.Ala258Val Uncertain significance ★ ⚠ same type
RNPEP p.Ala339Thr Uncertain significance ★ ⚠ same type
RNPEP p.Ala354Thr Uncertain significance ★ ⚠ same type
RNPEP p.Ala365Thr Uncertain significance ★ ⚠ same type
RNPEP p.Arg176Trp Uncertain significance ★ ⚠ same type
RNPEP p.Arg376Gln 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/rnpep-p-val397met (accessed [today's date]).

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