Is PRF1 p.Met1Val (c.1A>G) pathogenic?

PRF1 p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in PRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-22). Very rare (popmax 0.00228%, eas); Associated with hereditary hemophagocytic lymphohistiocytosis.

What condition is associated with PRF1 p.Met1Val (c.1A>G)?

PRF1 p.Met1Val (c.1A>G) is associated with hereditary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Met1Val (c.1A>G) in the general population?

PRF1 p.Met1Val (c.1A>G) is very rare (popmax 0.00228%, eas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

PRF1 p.Met1Val

c.1A>G · rs1848222357 · VCV1029054

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Conditions

hereditary hemophagocytic lymphohistiocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.636	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 1
Overall
CADD	20.9	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

Grpmax group 0.00228% East Asian · 1/43,952 alleles

Overall 0.00019% 3/1,582,598 alleles · very rare exomes 3/1,430,374 · genomes 0/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,952
African / African-American	0.00134%	74,782
European (non-Finnish)	8.58e-05%	1,165,750

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.Met1Val
Coding: c.1A>G
MANE Select: NM_001083116
dbSNP: rs1848222357
Type: single nucleotide variant
Location: chr10:70600902 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01

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

Disease context

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

Also linked: familial hemophagocytic lymphohistiocytosis 2

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

PRF1 p.Met1Ile Pathogenic/Likely pathogenic ★★ same residue
PRF1 p.Met1Leu Pathogenic ★ same residue
PRF1 p.Met1Thr Pathogenic ★ 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

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-met1val (accessed [today's date]).

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