Is DCC p.Thr463Met (c.1388C>T) pathogenic?

DCC p.Thr463Met (c.1388C>T) is classified Uncertain significance in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-12). AlphaMissense: ambiguous (0.4726); Ultra-rare (popmax 0.0973%, afr).

How common is DCC p.Thr463Met (c.1388C>T) in the general population?

DCC p.Thr463Met (c.1388C>T) is ultra-rare (popmax 0.0973%, afr) (gnomAD).

What do computational predictors say about DCC p.Thr463Met (c.1388C>T)?

AlphaMissense predicts ambiguous (score 0.4726) — an in-silico prediction, not a clinical call.

DCC p.Thr463Met

c.1388C>T · VCV4529748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0973%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4726	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -5.88	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	25.6	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 0.0973% African / African-American · 73/75,044 alleles

Filtering AF 0.0793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0727%

Overall 0.00997% 161/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0973%	1,028
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0304%	3,290
South Asian	0.0143%	7,006
Admixed American	0.00667%	15,003
East Asian	0.00446%	22,438
European (non-Finnish)	0.00373%	26,818
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Thr463Met
Coding: c.1388C>T
MANE Select: NM_005215
Type: single nucleotide variant
Location: chr18:53157482 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 463: a UniProt-annotated variant site (in mrmv1; likely pathogenic); a β-strand; the fibronectin type-iii 1 domain

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

Similar variants

DCC p.Arg1021Ter Pathogenic ★★ same type
DCC p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same type
DCC p.Arg275Ter Pathogenic ★★ same type
DCC p.Arg879Ter Pathogenic/Likely pathogenic ★★ same type
DCC c.3620-2A>G Uncertain significance ★★ same type
DCC p.Arg597Gln Uncertain significance ★★ ⚠ same type
DCC p.Gly1294Arg Uncertain significance ★★ ⚠ same type
DCC p.Gly55Arg 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/dcc-p-thr463met (accessed [today's date]).

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