Is PRORP p.Phe84Val (c.250T>G) pathogenic?

PRORP p.Phe84Val (c.250T>G) is classified Uncertain significance in PRORP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-28). AlphaMissense: likely benign (0.053); Very rare (popmax 0.000763%, nfe).

How common is PRORP p.Phe84Val (c.250T>G) in the general population?

PRORP p.Phe84Val (c.250T>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about PRORP p.Phe84Val (c.250T>G)?

AlphaMissense predicts likely benign (score 0.053) — an in-silico prediction, not a clinical call.

PRORP p.Phe84Val

c.250T>G · rs2046999084 · VCV3219070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.053	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.11	GERP -3.8, phastCons 0.003
Regional constraint	o/e 0.94	unconstrained · MANE · 150 kb · p 0.092 · regional, not allelic
Overall
CADD	5.477	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 0.000763% European (non-Finnish) · 9/1,179,766 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,672 alleles · very rare exomes 9/1,461,610 · genomes 0/152,062 · 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: PRORP
Protein: p.Phe84Val
Coding: c.250T>G
MANE Select: NM_014672
dbSNP: rs2046999084
Type: single nucleotide variant
Location: chr14:35123495 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.19 · 5 PDB

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

Similar variants

PRORP p.Arg421Cys Uncertain significance ★★ ⚠ same type
PRORP p.Arg502Gln Uncertain significance ★★ ⚠ same type
PRORP p.Asn412Ser Uncertain significance ★★ ⚠ same type
PRORP p.Lys76= Likely benign ★★ same type
PRORP p.Ala434Asp Likely pathogenic ★ ⚠ same type
PRORP c.-1A>G Uncertain significance ★ same type
PRORP p.Ala104Val Uncertain significance ★ ⚠ same type
PRORP p.Ala158Thr 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/prorp-p-phe84val (accessed [today's date]).

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