Is PRF1 p.Asp49Val (c.146A>T) pathogenic?

PRF1 p.Asp49Val (c.146A>T) is classified Likely pathogenic in PRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.8172); Very rare (popmax 0.00305%, nfe); Associated with familial hemophagocytic lymphohistiocytosis 2.

What condition is associated with PRF1 p.Asp49Val (c.146A>T)?

PRF1 p.Asp49Val (c.146A>T) is associated with familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Asp49Val (c.146A>T) in the general population?

PRF1 p.Asp49Val (c.146A>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

What do computational predictors say about PRF1 p.Asp49Val (c.146A>T)?

AlphaMissense predicts likely pathogenic (score 0.8172) — an in-silico prediction, not a clinical call.

PRF1 p.Asp49Val

c.146A>T · VCV4691823

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 2

Computational evidence

Protein change
AlphaMissense	0.8172	likely pathogenic ✓ concordant with ClinVar · top 8% in PRF1
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -12.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	25.8	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 0.00305% European (non-Finnish) · 36/1,178,856 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0023% 37/1,612,066 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00305%	32,746
Remaining individualsnot grpmax-eligible	0.0016%	62,368

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.Asp49Val
Coding: c.146A>T
MANE Select: NM_001083116
Type: single nucleotide variant
Location: chr10:70600757 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 49: a disulfide bond; the macpf 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 p.Asp49Glu Likely pathogenic ★★ ⚠ same residue
PRF1 p.Asp49= Likely benign ★ same residue
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

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-asp49val (accessed [today's date]).

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