Is PF4 p.Cys67Phe (c.200G>T) pathogenic?

PF4 p.Cys67Phe (c.200G>T) is classified Uncertain significance in PF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely pathogenic (0.8617); Very rare (popmax 8.47e-05%, nfe).

How common is PF4 p.Cys67Phe (c.200G>T) in the general population?

PF4 p.Cys67Phe (c.200G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PF4 p.Cys67Phe (c.200G>T)?

AlphaMissense predicts likely pathogenic (score 0.8617) — an in-silico prediction, not a clinical call.

PF4 p.Cys67Phe

c.200G>T · rs1718785021 · VCV2488863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8617	likely pathogenic · top 4% in PF4
REVEL	0.579	indeterminate
SaProt	LLR -8.97	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 746 bp · p 0.28 · regional, not allelic
Overall
CADD	28.3	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 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,880 · genomes 0/152,312 · joint denominator

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: PF4
Protein: p.Cys67Phe
Coding: c.200G>T
MANE Select: NM_002619
dbSNP: rs1718785021
Type: single nucleotide variant
Location: chr4:73981435 (GRCh38)
Gene constraint: LOEUF 1.899 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 10 PDB
Residue 67: a β-strand; a disulfide bond

Full PF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PF4 p.Leu72= Benign ★★ same type
PF4 p.Ala5Thr Uncertain significance ★ ⚠ same type
PF4 p.Arg51Cys Uncertain significance ★ ⚠ same type
PF4 p.Glu59Gln Uncertain significance ★ ⚠ same type
PF4 p.Gly13Glu Uncertain significance ★ ⚠ same type
PF4 p.Gly18Arg Uncertain significance ★ ⚠ same type
PF4 p.Gly37Val Uncertain significance ★ ⚠ same type
PF4 p.Gly64Arg Uncertain significance ★ ⚠ same type

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/pf4-p-cys67phe (accessed [today's date]).

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