Is PGF p.Arg134Trp (c.400C>T) pathogenic?

PGF p.Arg134Trp (c.400C>T) is classified Uncertain significance in PGF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.1099); Ultra-rare (popmax 0.0331%, mid).

How common is PGF p.Arg134Trp (c.400C>T) in the general population?

PGF p.Arg134Trp (c.400C>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about PGF p.Arg134Trp (c.400C>T)?

AlphaMissense predicts likely benign (score 0.1099) — an in-silico prediction, not a clinical call.

PGF p.Arg134Trp

c.400C>T · rs142448465 · VCV2220622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1099	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -8.09	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 -0.21	GERP -3.3
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	15.54	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R206W vs ClinVar R134W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,040 alleles

Filtering AF 0.00704% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00653%

Overall 0.0112% 181/1,610,410 alleles · ultra-rare exomes 156/1,458,072 · genomes 25/152,338 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0985%	1,015
Middle Easterngrpmax	0.0331%	3,020
Remaining individualsnot grpmax-eligible	0.0112%	8,900
African / African-American	0.0107%	9,372
European (non-Finnish)	0.00841%	11,897
East Asian	0.00223%	44,818
South Asian	0.00111%	90,456

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PGF
Protein: p.Arg134Trp
Coding: c.400C>T
MANE Select: NM_002632
dbSNP: rs142448465
Type: single nucleotide variant
Location: chr14:74946401 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 71.00 · 2 PDB
Residue 206 UniProt numbering: the 'disordered' region; the 'heparin-binding' region

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

Similar variants

PGF p.Arg134Gln Uncertain significance ★ ⚠ same residue
PIGF p.Asn134= Likely benign ★ same residue
PIGF p.Cys83Trp Uncertain significance ★★ same type
PIGF p.Val62Ala Benign ★★ same type
PGF p.Ala21Thr Uncertain significance ★ ⚠ same type
PGF p.Ala54Val Uncertain significance ★ ⚠ same type
PGF p.Arg110Leu Uncertain significance ★ ⚠ same type
PGF p.Arg114Trp 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/pgf-p-arg134trp (accessed [today's date]).

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