Is DCC p.Gln460His (c.1380A>C) pathogenic?

DCC p.Gln460His (c.1380A>C) is classified Benign in DCC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-30). AlphaMissense: ambiguous (0.5011); Rare (popmax 0.722%, eas); Associated with DCC-related disorder.

What condition is associated with DCC p.Gln460His (c.1380A>C)?

DCC p.Gln460His (c.1380A>C) is associated with DCC-related disorder (ClinVar).

How common is DCC p.Gln460His (c.1380A>C) in the general population?

DCC p.Gln460His (c.1380A>C) is rare (popmax 0.722%, eas) (gnomAD).

What do computational predictors say about DCC p.Gln460His (c.1380A>C)?

AlphaMissense predicts ambiguous (score 0.5011) — an in-silico prediction, not a clinical call.

DCC p.Gln460His

c.1380A>C · rs199848449 · VCV3033426

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5011 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.722%, eas)

Conditions

DCC-related disorder

Computational evidence

Protein change
AlphaMissense	0.5011	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -6.85	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	18.36	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 0.722% East Asian · 324/44,870 alleles

Filtering AF 0.657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.632%

Overall 0.024% 388/1,614,108 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.722%	138
Remaining individualsnot grpmax-eligible	0.0736%	1,359
South Asian	0.0143%	7,006
Admixed American	0.00333%	30,009
African / African-American	0.00133%	75,036
European (non-Finnish)	0.000169%	589,998

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.Gln460His
Coding: c.1380A>C
MANE Select: NM_005215
dbSNP: rs199848449
Type: single nucleotide variant
Location: chr18:53157474 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 460: 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

Disease context

DCC-related disorder

Similar variants

DCC c.2828-1G>A Likely pathogenic ★ same condition
DCC c.3898+2T>C Likely pathogenic ★ same condition
DCC p.Arg501Ter Likely pathogenic ★ same condition
DCC p.Glu512Ter Likely pathogenic ★ same condition
DCC p.Trp508Ter Likely pathogenic ★ same condition
DCC p.Trp745Ter Likely pathogenic ★ same condition
DCC p.Pro1086Leu Uncertain significance ⚠ same condition
DCC p.Thr614Ile Uncertain significance ⚠ 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-gln460his (accessed [today's date]).

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