Is PRF1 p.Ala235Val (c.704C>T) pathogenic?

PRF1 p.Ala235Val (c.704C>T) is classified Uncertain significance in PRF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1224); Ultra-rare (popmax 0.0155%, nfe); Associated with PRF1-related disorder.

What condition is associated with PRF1 p.Ala235Val (c.704C>T)?

PRF1 p.Ala235Val (c.704C>T) is associated with PRF1-related disorder, familial hemophagocytic lymphohistiocytosis 2 (ClinVar).

How common is PRF1 p.Ala235Val (c.704C>T) in the general population?

PRF1 p.Ala235Val (c.704C>T) is ultra-rare (popmax 0.0155%, nfe) (gnomAD).

What do computational predictors say about PRF1 p.Ala235Val (c.704C>T)?

AlphaMissense predicts likely benign (score 0.1224) — an in-silico prediction, not a clinical call.

PRF1 p.Ala235Val

c.704C>T · rs142403457 · VCV965669

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1224 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PRF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1224	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.29, phastCons 0.97
Regional constraint	o/e 0.97	unconstrained · MANE · 2,846 bp · p 0.42 · regional, not allelic
Overall
CADD	15.64	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 0.0155% European (non-Finnish) · 183/1,179,730 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0119% 192/1,613,686 alleles · ultra-rare exomes 169/1,461,430 · genomes 23/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,447
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00133%	74,942

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.Ala235Val
Coding: c.704C>T
MANE Select: NM_001083116
dbSNP: rs142403457
Type: single nucleotide variant
Location: chr10:70599017 (GRCh38)
Gene constraint: LOEUF 1.438 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.01
Residue 235: the macpf domain

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

Disease context

PRF1-related disorder

Also linked: familial hemophagocytic lymphohistiocytosis 2

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-ala235val (accessed [today's date]).

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