Is PRF1 p.Pro389Ser (c.1165C>T) pathogenic?

PRF1 p.Pro389Ser (c.1165C>T) is classified Uncertain significance in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely benign (0.073); Very rare (popmax 0.00339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRF1 p.Pro389Ser (c.1165C>T)?

PRF1 p.Pro389Ser (c.1165C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRF1 p.Pro389Ser (c.1165C>T) in the general population?

PRF1 p.Pro389Ser (c.1165C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about PRF1 p.Pro389Ser (c.1165C>T)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

PRF1 p.Pro389Ser

c.1165C>T · rs376289273 · VCV2591544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -7.90	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 0.19	GERP -1.4
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	1.563	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 0.00339% European (non-Finnish) · 40/1,179,808 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00273% 44/1,612,838 alleles · very rare exomes 42/1,460,664 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,495
Remaining individualsnot grpmax-eligible	0.0032%	31,229
African / African-American	0.00133%	74,922
South Asian	0.0011%	91,050

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.Pro389Ser
Coding: c.1165C>T
MANE Select: NM_001083116
dbSNP: rs376289273
Type: single nucleotide variant
Location: chr10:70598556 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 389: the egf-like domain

Full PRF1 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

Similar variants

PRF1 p.Gly149Ser Pathogenic ★★ ⚠ same condition
PRF1 p.Arg104Cys Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg123Cys Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg214Gly Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg464Trp Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg550Trp Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg55His Uncertain significance ★★ ⚠ same condition
PRF1 p.Arg96Trp 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/prf1-p-pro389ser (accessed [today's date]).

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