Is DDR2 p.His136= (c.408T>C) pathogenic?

DDR2 p.His136= (c.408T>C) is classified Conflicting classifications of pathogenicity in DDR2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). Low-frequency (popmax 3.26%, eas); Associated with connective tissue disorder.

What condition is associated with DDR2 p.His136= (c.408T>C)?

DDR2 p.His136= (c.408T>C) is associated with connective tissue disorder, spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (ClinVar).

How common is DDR2 p.His136= (c.408T>C) in the general population?

DDR2 p.His136= (c.408T>C) is low-frequency (popmax 3.26%, eas) (gnomAD).

DDR2 p.His136=

c.408T>C · rs2271305 · VCV197782

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.26%, eas)

Conditions

connective tissue disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -3.9
Overall
CADD	6.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.26% East Asian · 1,463/44,858 alleles

Filtering AF 3.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.07%

Overall 0.59% 9,529/1,613,896 alleles · low-frequency exomes 8,793/1,461,830 · genomes 736/152,066 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	3.26%	31
Finnishnot grpmax-eligible	0.928%	108
Ashkenazi Jewishnot grpmax-eligible	0.557%	179
European (non-Finnish)	0.557%	180
Remaining individualsnot grpmax-eligible	0.472%	212
South Asian	0.256%	391
Admixed American	0.22%	455
Middle Eastern	0.116%	866
African / African-American	0.0974%	1,027

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.His136=
Coding: c.408T>C
MANE Select: NM_006182
dbSNP: rs2271305
Type: single nucleotide variant
Location: chr1:162754846 (GRCh38)
Gene constraint: LOEUF 0.375 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.57 · 5 PDB
Residue 136: the f5/8 type c domain; a β-strand

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Similar variants

DDR2 p.Arg752Cys Likely pathogenic ★★ same condition
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
DDR2 p.Arg668His 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-his136 (accessed [today's date]).

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