Is AGPS p.Asp28Val (c.83A>T) pathogenic?

AGPS p.Asp28Val (c.83A>T) is classified Uncertain significance in AGPS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-24). AlphaMissense: likely benign (0.1044); Ultra-rare (popmax 0.0358%, mid); Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Asp28Val (c.83A>T)?

AGPS p.Asp28Val (c.83A>T) is associated with rhizomelic chondrodysplasia punctata type 3 (ClinVar).

How common is AGPS p.Asp28Val (c.83A>T) in the general population?

AGPS p.Asp28Val (c.83A>T) is ultra-rare (popmax 0.0358%, mid) (gnomAD).

How is Rhizomelic chondrodysplasia punctata inherited?

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

What do computational predictors say about AGPS p.Asp28Val (c.83A>T)?

AlphaMissense predicts likely benign (score 0.1044) — an in-silico prediction, not a clinical call.

AGPS p.Asp28Val

c.83A>T · rs764286061 · VCV332512

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
AlphaMissense	0.1044	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -9.62	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 0.56	GERP -0.24, phastCons 0.28
Regional constraint	o/e 1.09	unconstrained · MANE · 244 bp · p 0.32 · regional, not allelic
Overall
CADD	12.94	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0358% Middle Eastern · 2/5,586 alleles

Filtering AF 0.00628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00259%

Overall 0.00303% 47/1,549,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0358%	2,793
Admixed American	0.00975%	10,253
Remaining individualsnot grpmax-eligible	0.00333%	30,066
European (non-Finnish)	0.00322%	31,057
South Asian	0.00119%	84,276

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: AGPS
Protein: p.Asp28Val
Coding: c.83A>T
MANE Select: NM_003659
dbSNP: rs764286061
Type: single nucleotide variant
Location: chr2:177392872 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 28: the 'disordered' region

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

Disease context

rhizomelic chondrodysplasia punctata type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rhizomelic chondrodysplasia punctata (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

AGPS p.Asp28= Likely benign ★ same residue
AGPS p.Arg182Ter Pathogenic/Likely pathogenic ★★ same condition
AGPS p.Thr309Ile Likely pathogenic ★★ same condition
AGPS c.1855+6C>A Uncertain significance ★★ same condition
AGPS c.*118A>G Uncertain significance ★★ same condition
AGPS p.Pro415Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Thr72Ala Uncertain significance ★★ ⚠ same condition
AGPS c.1233+14T>A Benign/Likely benign ★★ 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/agps-p-asp28val (accessed [today's date]).

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