Is PRF1 p.Trp428Ser (c.1283G>C) pathogenic?

PRF1 p.Trp428Ser (c.1283G>C) is classified Uncertain significance in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely benign (0.3037); Very rare (popmax 0.00446%, eas).

How common is PRF1 p.Trp428Ser (c.1283G>C) in the general population?

PRF1 p.Trp428Ser (c.1283G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about PRF1 p.Trp428Ser (c.1283G>C)?

AlphaMissense predicts likely benign (score 0.3037) — an in-silico prediction, not a clinical call.

PRF1 p.Trp428Ser

c.1283G>C · rs747646127 · VCV2683110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3037	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -10.87	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP -1.1, phastCons 0.32
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	22.1	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 0.00446% East Asian · 2/44,866 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000248% 4/1,613,876 alleles · very rare exomes 4/1,461,554 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,433
Remaining individualsnot grpmax-eligible	0.0016%	62,512
Finnishnot grpmax-eligible	0.00157%	63,702

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: PRF1
Protein: p.Trp428Ser
Coding: c.1283G>C
MANE Select: NM_001083116
dbSNP: rs747646127
Type: single nucleotide variant
Location: chr10:70598438 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 428: the c2 domain

Full PRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRF1 p.Trp428Ter Likely pathogenic ★ same residue
PRF1 p.Trp428Leu Uncertain significance ★ same residue
PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same type
PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same type
PRF1 p.Arg232Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
PRF1 p.Arg299Cys Pathogenic/Likely pathogenic ★★ same type
PRF1 p.Arg356Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PRF1 p.Arg361Trp Pathogenic/Likely pathogenic ★★ ⚠ 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/prf1-p-trp428ser (accessed [today's date]).

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