Is DCC p.Lys419Arg (c.1256A>G) pathogenic?

DCC p.Lys419Arg (c.1256A>G) is classified Conflicting classifications of pathogenicity in DCC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1266); Rare (popmax 0.495%, nfe); Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

What condition is associated with DCC p.Lys419Arg (c.1256A>G)?

DCC p.Lys419Arg (c.1256A>G) is associated with gaze palsy, familial horizontal, with progressive scoliosis, 2 (ClinVar).

How common is DCC p.Lys419Arg (c.1256A>G) in the general population?

DCC p.Lys419Arg (c.1256A>G) is rare (popmax 0.495%, nfe) (gnomAD).

What do computational predictors say about DCC p.Lys419Arg (c.1256A>G)?

AlphaMissense predicts likely benign (score 0.1266) — an in-silico prediction, not a clinical call.

DCC p.Lys419Arg

Q: How is Horizontal gaze palsy with progressive scoliosis inherited?

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

c.1256A>G · rs144623089 · VCV719574

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1266 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.495%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

gaze palsy, familial horizontal, with progressive scoliosis, 2

Computational evidence

Protein change
AlphaMissense	0.1266	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	—	withheld · numbering disagrees past residue 178 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.495% European (non-Finnish) · 5,838/1,179,300 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.48%

Overall 0.407% 6,572/1,613,030 alleles · rare exomes 6,154/1,461,016 · genomes 418/152,014 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.769%	130
European (non-Finnish)grpmax	0.495%	202
Remaining individualsnot grpmax-eligible	0.328%	305
Finnishnot grpmax-eligible	0.263%	381
South Asian	0.247%	405
Admixed American	0.108%	922
African / African-American	0.08%	1,249
Middle Eastern	0.0165%	6,056
East Asian	0.00446%	22,412
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588

Amish 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: DCC
Protein: p.Lys419Arg
Coding: c.1256A>G
MANE Select: NM_005215
dbSNP: rs144623089
Type: single nucleotide variant
Location: chr18:53066161 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 419: a UniProt-annotated variant site (in mrmv1; likely pathogenic)

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

Disease context

gaze palsy, familial horizontal, with progressive scoliosis, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Horizontal gaze palsy with progressive scoliosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

DCC c.2053+13A>G Benign ★★ same condition
DCC c.2053+9T>C Benign/Likely benign ★★ same condition
DCC c.3130+10A>G Benign ★★ same condition
DCC c.91+7G>A Benign ★★ same condition
DCC p.Arg201Gly Benign ★★ same condition
DCC p.Glu118= Benign ★★ same condition
DCC p.Leu720= Benign/Likely benign ★★ same condition
DCC p.Phe23Leu Benign ★★ ⚠ 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/dcc-p-lys419arg (accessed [today's date]).

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