Is DCC p.Ala257Thr (c.769G>A) pathogenic?

DCC p.Ala257Thr (c.769G>A) is classified Uncertain significance in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-14). AlphaMissense: likely benign (0.1802); Absent from gnomAD v4.1; Associated with gaze palsy, familial horizontal, with progressive scoliosis, 2.

What condition is associated with DCC p.Ala257Thr (c.769G>A)?

DCC p.Ala257Thr (c.769G>A) is associated with gaze palsy, familial horizontal, with progressive scoliosis, 2 (ClinVar).

How common is DCC p.Ala257Thr (c.769G>A) in the general population?

DCC p.Ala257Thr (c.769G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DCC p.Ala257Thr (c.769G>A)?

AlphaMissense predicts likely benign (score 0.1802) — an in-silico prediction, not a clinical call.

DCC p.Ala257Thr

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.769G>A · rs2040159710 · VCV930503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1802 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

gaze palsy, familial horizontal, with progressive scoliosis, 2

Computational evidence

Protein change
AlphaMissense	0.1802	likely benign
REVEL	0.559	indeterminate
SaProt	LLR -8.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	24.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DCC
Protein: p.Ala257Thr
Coding: c.769G>A
MANE Select: NM_005215
dbSNP: rs2040159710
Type: single nucleotide variant
Location: chr18:52923778 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 257: the ig-like c2-type 3 domain

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-ala257thr (accessed [today's date]).

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