Is PRPF8 p.Met1237Val (c.3709A>G) pathogenic?

PRPF8 p.Met1237Val (c.3709A>G) is classified Uncertain significance in PRPF8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-22). AlphaMissense: likely benign (0.1392); Very rare (popmax 0.00178%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRPF8 p.Met1237Val (c.3709A>G)?

PRPF8 p.Met1237Val (c.3709A>G) is associated with Inborn genetic diseases, retinitis pigmentosa 13 (ClinVar).

How common is PRPF8 p.Met1237Val (c.3709A>G) in the general population?

PRPF8 p.Met1237Val (c.3709A>G) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about PRPF8 p.Met1237Val (c.3709A>G)?

AlphaMissense predicts likely benign (score 0.1392) — an in-silico prediction, not a clinical call.

PRPF8 p.Met1237Val

c.3709A>G · rs1053250821 · VCV953303

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1392 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1392	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -7.31	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 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 41 bp · p 0.57 · regional, not allelic
Overall
CADD	21.7	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 0.00178% European (non-Finnish) · 21/1,180,036 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00142% 23/1,614,086 alleles · very rare exomes 22/1,461,894 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00178%	56,192
Finnishnot grpmax-eligible	0.00156%	64,048
South Asian	0.0011%	91,088

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: PRPF8
Protein: p.Met1237Val
Coding: c.3709A>G
MANE Select: NM_006445
dbSNP: rs1053250821
Type: single nucleotide variant
Location: chr17:1673146 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.20 · 100 PDB
Residue 1237: an α-helix; the 'reverse transcriptase homology domain' region

Full PRPF8 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

Also linked: retinitis pigmentosa 13

Similar variants

PRPF8 p.Arg1935His Pathogenic/Likely pathogenic ★★ same condition
PRPF8 p.Arg2310Gly Pathogenic/Likely pathogenic ★★ same condition
PRPF8 p.Arg2310Lys Pathogenic ★★ ⚠ same condition
PRPF8 p.His2309Arg Pathogenic ★★ ⚠ same condition
PRPF8 p.His2309Pro Pathogenic/Likely pathogenic ★★ same condition
PRPF8 p.Thr1931Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRPF8 p.Tyr2326Ter Pathogenic/Likely pathogenic ★★ same condition
PRPF8 c.1719+4A>G 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/prpf8-p-met1237val (accessed [today's date]).

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