Is DDR2 p.Arg752Cys (c.2254C>T) pathogenic?

DDR2 p.Arg752Cys (c.2254C>T) is classified Likely pathogenic in DDR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-16). AlphaMissense: likely pathogenic (0.9911); Very rare (popmax 0.000508%, nfe); Associated with spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome.

What condition is associated with DDR2 p.Arg752Cys (c.2254C>T)?

DDR2 p.Arg752Cys (c.2254C>T) is associated with spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (ClinVar).

How common is DDR2 p.Arg752Cys (c.2254C>T) in the general population?

DDR2 p.Arg752Cys (c.2254C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about DDR2 p.Arg752Cys (c.2254C>T)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

DDR2 p.Arg752Cys

Q: How is Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome inherited?

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

c.2254C>T · rs121964863 · VCV12313

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic ✓ concordant with ClinVar · top 8% in DDR2
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -16.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 8,206 bp · p 2.1e-15 · regional, not allelic
Overall
CADD	33.0	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 0.000508% European (non-Finnish) · 6/1,179,958 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,070 alleles · very rare exomes 6/1,461,770 · genomes 0/152,300 · 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: DDR2
Protein: p.Arg752Cys
Coding: c.2254C>T
MANE Select: NM_006182
dbSNP: rs121964863
Type: single nucleotide variant
Location: chr1:162776341 (GRCh38)
Gene constraint: LOEUF 0.375 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.57 · 5 PDB
Residue 752: a UniProt-annotated variant site (in semd-sl; causes retention in an intracellular compartment and thereby abolishes signaling in response collagen binding); the protein kinase domain; a turn

Full DDR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DDR2 p.Arg752His Uncertain significance ★★ ⚠ same residue
DDR2 p.Arg752Ser Uncertain significance ★ ⚠ same residue
DDR2 c.-27-11G>C Uncertain significance ★★ same condition
DDR2 c.*48A>G Uncertain significance ★★ same condition
DDR2 p.Arg128His Uncertain significance ★★ ⚠ same condition
DDR2 p.Arg165Gln Uncertain significance ★★ ⚠ same condition
DDR2 p.Arg260Trp Uncertain significance ★★ ⚠ same condition
DDR2 p.Arg307Cys 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/ddr2-p-arg752cys (accessed [today's date]).

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