Is AGPS p.Ala67Val (c.200C>T) pathogenic?

AGPS p.Ala67Val (c.200C>T) is classified Uncertain significance in AGPS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-10-13). AlphaMissense: likely benign (0.0965); Very rare (popmax 0.00978%, eas); Associated with rhizomelic chondrodysplasia punctata.

What condition is associated with AGPS p.Ala67Val (c.200C>T)?

AGPS p.Ala67Val (c.200C>T) is associated with rhizomelic chondrodysplasia punctata (ClinVar).

How common is AGPS p.Ala67Val (c.200C>T) in the general population?

AGPS p.Ala67Val (c.200C>T) is very rare (popmax 0.00978%, eas) (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.Ala67Val (c.200C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

AGPS p.Ala67Val

c.200C>T · rs1454806934 · VCV991242

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00978%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rhizomelic chondrodysplasia punctata

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -7.99	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 4.3	GERP -0.12, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 244 bp · p 0.32 · regional, not allelic
Overall
CADD	21.1	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 0.00978% East Asian · 4/40,882 alleles

Filtering AF 0.00328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00193%

Overall 0.000286% 4/1,397,784 alleles · very rare

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.Ala67Val
Coding: c.200C>T
MANE Select: NM_003659
dbSNP: rs1454806934
Type: single nucleotide variant
Location: chr2:177392989 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 67: the 'disordered' region

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

Disease context

rhizomelic chondrodysplasia punctata — 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.Ala67= Likely benign ★ same residue
AGPS p.Thr309Ile Likely pathogenic ★★ same condition
AGPS c.261-5A>C Benign ★★ same condition
AGPS p.Ala69= Benign ★★ same condition
AGPS p.His362= Likely benign ★★ same condition
AGPS p.Pro415= Benign/Likely benign ★★ same condition
AGPS p.Pro49= Benign/Likely benign ★★ same condition
AGPS p.Ala5Val 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/agps-p-ala67val (accessed [today's date]).

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