Is DCC p.Phe23Leu (c.67T>C) pathogenic?

DCC p.Phe23Leu (c.67T>C) is classified Benign in DCC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-28). AlphaMissense: likely pathogenic (0.5796); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

What condition is associated with DCC p.Phe23Leu (c.67T>C)?

DCC p.Phe23Leu (c.67T>C) is associated with gaze palsy, familial horizontal, with progressive scoliosis, 2 (ClinVar).

What do computational predictors say about DCC p.Phe23Leu (c.67T>C)?

AlphaMissense predicts likely pathogenic (score 0.5796) — an in-silico prediction, not a clinical call.

DCC p.Phe23Leu

Q: How common is DCC p.Phe23Leu (c.67T>C) in the general population?

DCC p.Phe23Leu (c.67T>C) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.67T>C · rs9951523 · VCV1255454

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5796 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gaze palsy, familial horizontal, with progressive scoliosis, 2

Computational evidence

Protein change
AlphaMissense	0.5796	likely pathogenic
REVEL	0.099	moderately benign-leaning
SaProt	LLR -4.43	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.73, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	18.55	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 100% East Asian · 44,833/44,838 alleles

Filtering AF 99.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.1%

Overall 98.6% 1,591,522/1,613,996 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
South Asian	99.9%	1
African / African-American	99.8%	1
Admixed American	99.3%	1
Middle Eastern	98.9%	1
Remaining individualsnot grpmax-eligible	98.7%	1
European (non-Finnish)	98.6%	1
Amishnot grpmax-eligible	97.9%	1
Ashkenazi Jewishnot grpmax-eligible	97.4%	1
Finnishnot grpmax-eligible	95.1%	1

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.Phe23Leu
Coding: c.67T>C
MANE Select: NM_005215
dbSNP: rs9951523
Type: single nucleotide variant
Location: chr18:52340854 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 23: a UniProt-annotated variant site (in)

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:

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-phe23leu (accessed [today's date]).

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