Is PLG p.Asp665Val (c.1994A>T) pathogenic?

PLG p.Asp665Val (c.1994A>T) is classified Likely pathogenic in PLG (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-13). AlphaMissense: likely pathogenic (0.9851); Ultra-rare (popmax 0.0165%, mid); Associated with hypoplasminogenemia.

What condition is associated with PLG p.Asp665Val (c.1994A>T)?

PLG p.Asp665Val (c.1994A>T) is associated with hypoplasminogenemia (ClinVar).

How common is PLG p.Asp665Val (c.1994A>T) in the general population?

PLG p.Asp665Val (c.1994A>T) is ultra-rare (popmax 0.0165%, mid) (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.Asp665Val (c.1994A>T)?

AlphaMissense predicts likely pathogenic (score 0.9851) — an in-silico prediction, not a clinical call.

PLG p.Asp665Val

c.1994A>T · VCV4820655

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypoplasminogenemia

Computational evidence

Protein change
AlphaMissense	0.9851	likely pathogenic ✓ concordant with ClinVar · top 4% in PLG
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -13.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.96 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 50 kb · p 0.011 · regional, not allelic
Overall
CADD	25.7	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.2e-05% 1/1,614,150 alleles · ultra-rare exomes 1/1,461,888 · genomes 0/152,262 · 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.Asp665Val
Coding: c.1994A>T
MANE Select: NM_000301
Type: single nucleotide variant
Location: chr6:160739184 (GRCh38)
Gene constraint: LOEUF 0.559 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.53 · 49 PDB
Residue 665: the peptidase s1 domain; an active site

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.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
PLG p.Arg172Gly 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-asp665val (accessed [today's date]).

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