Is PDF p.Arg76His (c.227G>A) pathogenic?

PDF p.Arg76His (c.227G>A) is classified Uncertain significance in PDF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.5755); Very rare (popmax 0.00147%, afr).

How common is PDF p.Arg76His (c.227G>A) in the general population?

PDF p.Arg76His (c.227G>A) is very rare (popmax 0.00147%, afr) (gnomAD).

What do computational predictors say about PDF p.Arg76His (c.227G>A)?

AlphaMissense predicts likely pathogenic (score 0.5755) — an in-silico prediction, not a clinical call.

PDF p.Arg76His

c.227G>A · rs2011700226 · VCV3210814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00147%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5755	likely pathogenic
REVEL	0.431	indeterminate
SaProt	LLR -10.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 1,545 bp · p 9e-06 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00147% African / African-American · 1/68,152 alleles

Overall 0.000136% 2/1,468,896 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00176%	56,728
African / African-Americangrpmax	0.00147%	68,152

Remaining individuals 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: PDF
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_032382 · reported on NM_022341
dbSNP: rs2011700226
Type: single nucleotide variant
Location: chr16:69330344 (GRCh38)

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

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/pdf-p-arg76his (accessed [today's date]).

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