Is AGPS p.Ala5Val (c.14C>T) pathogenic?

AGPS p.Ala5Val (c.14C>T) is classified Uncertain significance in AGPS (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-12). AlphaMissense: likely benign (0.3168); Very rare (popmax 0.00145%, afr); Associated with rhizomelic chondrodysplasia punctata type 3.

What condition is associated with AGPS p.Ala5Val (c.14C>T)?

AGPS p.Ala5Val (c.14C>T) is associated with rhizomelic chondrodysplasia punctata type 3, rhizomelic chondrodysplasia punctata (ClinVar).

How common is AGPS p.Ala5Val (c.14C>T) in the general population?

AGPS p.Ala5Val (c.14C>T) is very rare (popmax 0.00145%, afr) (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.Ala5Val (c.14C>T)?

AlphaMissense predicts likely benign (score 0.3168) — an in-silico prediction, not a clinical call.

AGPS p.Ala5Val

c.14C>T · rs1233318758 · VCV893624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00145%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

rhizomelic chondrodysplasia punctata type 3

Computational evidence

Protein change
AlphaMissense	0.3168	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -8.61	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 -0.25	GERP -3, phastCons 0.021
Regional constraint	o/e 1.09	unconstrained · MANE · 244 bp · p 0.32 · regional, not allelic
Overall
CADD	18.16	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 0.00145% African / African-American · 1/69,146 alleles

Filtering AF 0.000189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000125%

Overall 0.000598% 9/1,503,774 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00172%	57,988
African / African-Americangrpmax	0.00145%	69,146
South Asian	0.00132%	75,542
European (non-Finnish)	0.000527%	189,861

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala5Val
Coding: c.14C>T
MANE Select: NM_003659
dbSNP: rs1233318758
Type: single nucleotide variant
Location: chr2:177392803 (GRCh38)
Gene constraint: LOEUF 0.408 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.27
Residue 5: 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

Also linked: rhizomelic chondrodysplasia punctata

For Rhizomelic chondrodysplasia punctata (Orphanet):

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

Similar variants

AGPS p.Ala5= 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.Asp28Val Uncertain significance ★★ ⚠ same condition
AGPS p.Pro415Leu Uncertain significance ★★ ⚠ same condition
AGPS p.Thr72Ala 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-ala5val (accessed [today's date]).

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