Is PRPF4 p.Ala2Val (c.5C>T) pathogenic?

PRPF4 p.Ala2Val (c.5C>T) is classified Uncertain significance in PRPF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.2188); Very rare (popmax 6.2e-05%); Associated with inherited retinal dystrophy.

What condition is associated with PRPF4 p.Ala2Val (c.5C>T)?

PRPF4 p.Ala2Val (c.5C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is PRPF4 p.Ala2Val (c.5C>T) in the general population?

PRPF4 p.Ala2Val (c.5C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about PRPF4 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2188) — an in-silico prediction, not a clinical call.

PRPF4 p.Ala2Val

c.5C>T · VCV3249144

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2188 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.2188	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -8.34	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 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 16 kb · p 6e-12 · regional, not allelic
Overall
CADD	24.3	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 6.2e-05%

Overall 6.2e-05% 1/1,612,294 alleles · very rare exomes 1/1,459,964 · genomes 0/152,330 · 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: PRPF4
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_001244926
Type: single nucleotide variant
Location: chr9:113275748 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.33 · 25 PDB
Residue 2: the 'disordered' region

Full PRPF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRPF4 p.Ala2Thr Uncertain significance ★ ⚠ same residue
PRPF4 p.Pro314Leu Likely pathogenic ★★ same condition
PRPF4 p.Thr247Ala Conflicting classifications of pathogenicity ★ same condition
PRPF4 p.Thr443Ile Conflicting classifications of pathogenicity ★ same condition
PRPF4 p.Thr285Ile Uncertain significance same condition
PRPF4 p.Tyr161Cys Uncertain significance ⚠ same condition
PRPF4 c.654+4A>T Uncertain significance ★★ same type
PRPF4 p.Ala195Thr 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/prpf4-p-ala2val (accessed [today's date]).

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