Is PLG p.Arg235His (c.704G>A) pathogenic?

PLG p.Arg235His (c.704G>A) is classified Pathogenic in PLG (ClinVar, No assertion criteria, 1 submitter; last evaluated 1999-05-15). AlphaMissense: ambiguous (0.4301); Very rare (popmax 0.000848%, nfe); Associated with hypoplasminogenemia.

What condition is associated with PLG p.Arg235His (c.704G>A)?

PLG p.Arg235His (c.704G>A) is associated with hypoplasminogenemia (ClinVar).

How common is PLG p.Arg235His (c.704G>A) in the general population?

PLG p.Arg235His (c.704G>A) is very rare (popmax 0.000848%, nfe) (gnomAD).

How is Hypoplasminogenemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PLG p.Arg235His (c.704G>A)?

AlphaMissense predicts ambiguous (score 0.4301) — an in-silico prediction, not a clinical call.

PLG p.Arg235His

c.704G>A · rs121918030 · VCV13577

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hypoplasminogenemia

Computational evidence

Protein change
AlphaMissense	0.4301	ambiguous
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -14.27	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	33.0	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 0.000848% European (non-Finnish) · 10/1,179,032 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,018 alleles · very rare exomes 10/1,460,760 · genomes 0/152,258 · 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: PLG
Protein: p.Arg235His
Coding: c.704G>A
MANE Select: NM_000301
dbSNP: rs121918030
Type: single nucleotide variant
Location: chr6:160716680 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 235: a UniProt-annotated variant site (in plgd; severe type 1 deficiency); the kringle 2 domain

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

Disease context

hypoplasminogenemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypoplasminogenemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

PLG p.Arg235Cys Uncertain significance ★ ⚠ same residue
PLG p.Lys330Glu Pathogenic ★★ ⚠ same condition
PLG p.Lys38Glu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PLG c.669-3C>G Uncertain significance ★★ same condition
PLG p.Ala216Thr Uncertain significance ★★ ⚠ same condition
PLG p.Ala494Glu Uncertain significance ★★ ⚠ same condition
PLG p.Ala507Val Uncertain significance ★★ ⚠ same condition
PLG p.Ala675Val Uncertain significance ★★ ⚠ 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/plg-p-arg235his (accessed [today's date]).

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