Is DCC p.Leu720= (c.2158C>T) pathogenic?

DCC p.Leu720= (c.2158C>T) is classified Benign/Likely benign in DCC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-23). Rare (popmax 0.963%, afr); Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

How common is DCC p.Leu720= (c.2158C>T) in the general population?

DCC p.Leu720= (c.2158C>T) is rare (popmax 0.963%, afr) (gnomAD).

DCC p.Leu720=

Q: What condition is associated with DCC p.Leu720= (c.2158C>T)?

DCC p.Leu720= (c.2158C>T) is associated with gaze palsy, familial horizontal, with progressive scoliosis, 2, colorectal cancer, esophageal cancer (ClinVar).

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.2158C>T · rs138143831 · VCV714873

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.963%, afr)

Conditions

gaze palsy, familial horizontal, with progressive scoliosis, 2

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 4.1	GERP -0.83, phastCons 1
Overall
CADD	8.902	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.963% African / African-American · 700/72,716 alleles

Filtering AF 0.904% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.88%

Overall 0.0523% 782/1,495,572 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.963%	104
Remaining individualsnot grpmax-eligible	0.0785%	1,273
Admixed American	0.0451%	2,218
Middle Eastern	0.0343%	2,918
South Asian	0.00676%	14,789
European (non-Finnish)	9.33e-05%	1,071,840

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.Leu720=
Coding: c.2158C>T
MANE Select: NM_005215
dbSNP: rs138143831
Type: single nucleotide variant
Location: chr18:53322151 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 720: 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

Also linked: colorectal cancer esophageal cancer

For Horizontal gaze palsy with progressive scoliosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

DCC p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same condition
DCC p.Arg275Ter Pathogenic ★★ same condition
DCC p.Arg879Ter Pathogenic/Likely pathogenic ★★ same condition
DCC p.Gly803Arg Uncertain significance ★★ ⚠ same condition
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

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-leu720 (accessed [today's date]).

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