Is RPRD2 p.Val993Met (c.2977G>A) pathogenic?

RPRD2 p.Val993Met (c.2977G>A) is classified Uncertain significance in RPRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0694); Very rare (popmax 0.00446%, eas).

How common is RPRD2 p.Val993Met (c.2977G>A) in the general population?

RPRD2 p.Val993Met (c.2977G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about RPRD2 p.Val993Met (c.2977G>A)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

RPRD2 p.Val993Met

c.2977G>A · VCV3947607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.24	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 2.1	GERP -2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,086 bp · p 0.85 · regional, not allelic
Overall
CADD	16.81	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 0.00446% East Asian · 2/44,858 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00322% 52/1,613,730 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,429
European (non-Finnish)	0.00381%	26,219
Remaining individualsnot grpmax-eligible	0.0032%	31,234
African / African-American	0.00267%	37,444
South Asian	0.0011%	91,072

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: RPRD2
Protein: p.Val993Met
Coding: c.2977G>A
MANE Select: NM_015203
Type: single nucleotide variant
Location: chr1:150471925 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.32 · 3 PDB
Residue 993: the 'disordered' region

Full RPRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RPRD2 p.Glu195= Benign ★★ same type
RPRD2 p.Ala1083Ser Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1145Pro Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1149Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1165Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1251Thr Uncertain significance ★ ⚠ same type
RPRD2 p.Ala140Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala442Pro 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/rprd2-p-val993met (accessed [today's date]).

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