Is PRF1 p.Pro139Ser (c.415C>T) pathogenic?

PRF1 p.Pro139Ser (c.415C>T) is classified Uncertain significance in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.1217); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with PRF1 p.Pro139Ser (c.415C>T)?

PRF1 p.Pro139Ser (c.415C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRF1 p.Pro139Ser (c.415C>T) in the general population?

PRF1 p.Pro139Ser (c.415C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PRF1 p.Pro139Ser (c.415C>T)?

AlphaMissense predicts likely benign (score 0.1217) — an in-silico prediction, not a clinical call.

PRF1 p.Pro139Ser

c.415C>T · rs1404219127 · VCV3218600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1217	likely benign
REVEL	0.317	indeterminate
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	4.515	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 0.00167% Admixed American · 1/60,028 alleles

Overall 0.000124% 2/1,614,224 alleles · very rare exomes 2/1,461,878 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
Finnishnot grpmax-eligible	0.00156%	64,036

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.Pro139Ser
Coding: c.415C>T
MANE Select: NM_001083116
dbSNP: rs1404219127
Type: single nucleotide variant
Location: chr10:70600488 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 139: the macpf 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-pro139ser (accessed [today's date]).

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