Is PRF1 p.Ala437Val (c.1310C>T) pathogenic?

PRF1 p.Ala437Val (c.1310C>T) is classified Conflicting classifications of pathogenicity in PRF1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.5647); Rare (popmax 0.132%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRF1 p.Ala437Val (c.1310C>T)?

PRF1 p.Ala437Val (c.1310C>T) is associated with Inborn genetic diseases, familial hemophagocytic lymphohistiocytosis 2, autoinflammatory syndrome (ClinVar).

How common is PRF1 p.Ala437Val (c.1310C>T) in the general population?

PRF1 p.Ala437Val (c.1310C>T) is rare (popmax 0.132%, nfe) (gnomAD).

What do computational predictors say about PRF1 p.Ala437Val (c.1310C>T)?

AlphaMissense predicts likely pathogenic (score 0.5647) — an in-silico prediction, not a clinical call.

PRF1 p.Ala437Val

c.1310C>T · rs138126912 · VCV300327

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.5647 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5647	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	25.3	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 0.132% European (non-Finnish) · 1,562/1,180,014 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.108% 1,743/1,614,020 alleles · rare exomes 1,631/1,461,730 · genomes 112/152,290 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.132%	755
South Asian	0.116%	859
Remaining individualsnot grpmax-eligible	0.064%	1,563
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
African / African-American	0.016%	6,255
Finnishnot grpmax-eligible	0.0125%	7,984
Admixed American	0.005%	20,010

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.Ala437Val
Coding: c.1310C>T
MANE Select: NM_001083116
dbSNP: rs138126912
Type: single nucleotide variant
Location: chr10:70598411 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 437: the c2 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

Also linked: familial hemophagocytic lymphohistiocytosis 2 autoinflammatory syndrome

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-ala437val (accessed [today's date]).

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