Is AGPS p.Gln625Pro (c.1874A>C) pathogenic?

AGPS p.Gln625Pro (c.1874A>C) is classified Uncertain significance in AGPS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-08-26). AlphaMissense: likely benign (0.0986); Ultra-rare (popmax 0.0165%, mid); Associated with rhizomelic chondrodysplasia punctata.

What condition is associated with AGPS p.Gln625Pro (c.1874A>C)?

AGPS p.Gln625Pro (c.1874A>C) is associated with rhizomelic chondrodysplasia punctata (ClinVar).

How common is AGPS p.Gln625Pro (c.1874A>C) in the general population?

AGPS p.Gln625Pro (c.1874A>C) is ultra-rare (popmax 0.0165%, 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.Gln625Pro (c.1874A>C)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

AGPS p.Gln625Pro

c.1874A>C · rs769818292 · VCV991253

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

rhizomelic chondrodysplasia punctata

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.495	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 145 kb · p 9.9e-28 · regional, not allelic
Overall
CADD	22.2	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 0.0165% Middle Eastern · 1/6,056 alleles

Overall 0.000137% 2/1,460,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	8.48e-05%	1,179,344

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.Gln625Pro
Coding: c.1874A>C
MANE Select: NM_003659
dbSNP: rs769818292
Type: single nucleotide variant
Location: chr2:177538092 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27

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.Gln625= 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-gln625pro (accessed [today's date]).

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