Is PRF1 p.Ser462Ter (c.1385C>A) pathogenic?

PRF1 p.Ser462Ter (c.1385C>A) is classified Pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-01). No allele count reported in gnomAD v4.1 (AN 1,614,192); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Ser462Ter (c.1385C>A)?

PRF1 p.Ser462Ter (c.1385C>A) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Ser462Ter (c.1385C>A) in the general population?

PRF1 p.Ser462Ter (c.1385C>A) is no allele count reported in gnomAD v4.1 (AN 1,614,192) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

PRF1 p.Ser462Ter

c.1385C>A · rs1564723653 · VCV561093

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,192)

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.60	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -11	GERP -4
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,614,192). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PRF1
Protein: p.Ser462Ter
Coding: c.1385C>A
MANE Select: NM_001083116
dbSNP: rs1564723653
Type: single nucleotide variant
Location: chr10:70598336 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 462: the c2 domain

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

Disease context

familial hemophagocytic lymphohistiocytosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

PRF1 c.539+2T>A Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg225Trp Pathogenic ★★ ⚠ same condition
PRF1 p.Arg232Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg299Cys Pathogenic/Likely pathogenic ★★ same condition
PRF1 p.Arg356Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg361Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PRF1 p.Arg390Ter Pathogenic ★★ same condition
PRF1 p.Arg410Pro Pathogenic/Likely pathogenic ★★ 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-ser462ter (accessed [today's date]).

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