Is DDR2 p.Ser459Phe (c.1376C>T) pathogenic?

DDR2 p.Ser459Phe (c.1376C>T) is classified Uncertain significance in DDR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely benign (0.0995); Very rare (popmax 0.00834%, amr).

How common is DDR2 p.Ser459Phe (c.1376C>T) in the general population?

DDR2 p.Ser459Phe (c.1376C>T) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about DDR2 p.Ser459Phe (c.1376C>T)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

DDR2 p.Ser459Phe

c.1376C>T · rs750750022 · VCV1898466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 53 kb · p 4.1e-07 · regional, not allelic
Overall
CADD	25.8	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 0.00834% Admixed American · 5/59,986 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000558% 9/1,613,960 alleles · very rare exomes 8/1,461,890 · genomes 1/152,070 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,997
East Asian	0.00668%	14,965
European (non-Finnish)	8.47e-05%	1,180,018

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.Ser459Phe
Coding: c.1376C>T
MANE Select: NM_006182
dbSNP: rs750750022
Type: single nucleotide variant
Location: chr1:162770384 (GRCh38)
Gene constraint: LOEUF 0.375 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.57 · 5 PDB
Residue 459: the 'disordered' region

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

Similar variants

DDR2 p.Arg341Ter Pathogenic/Likely pathogenic ★★ same type
DDR2 p.Arg611Ter Pathogenic/Likely pathogenic ★★ same type
DDR2 p.Arg752Cys Likely pathogenic ★★ same type
DDR2 p.Leu610Pro Pathogenic/Likely pathogenic ★★ same type
DDR2 c.1728+6T>C Uncertain significance ★★ same type
DDR2 c.-27-11G>C Uncertain significance ★★ same type
DDR2 c.*48A>G Uncertain significance ★★ same type
DDR2 p.Arg128His Uncertain significance ★★ ⚠ same type

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-ser459phe (accessed [today's date]).

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