Is DCC p.Ile759Met (c.2277T>G) pathogenic?

DCC p.Ile759Met (c.2277T>G) is classified Benign in DCC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-30). AlphaMissense: likely benign (0.2706); Low-frequency (popmax 2.66%, eas); Associated with DCC-related disorder.

What condition is associated with DCC p.Ile759Met (c.2277T>G)?

DCC p.Ile759Met (c.2277T>G) is associated with DCC-related disorder (ClinVar).

How common is DCC p.Ile759Met (c.2277T>G) in the general population?

DCC p.Ile759Met (c.2277T>G) is low-frequency (popmax 2.66%, eas) (gnomAD).

What do computational predictors say about DCC p.Ile759Met (c.2277T>G)?

AlphaMissense predicts likely benign (score 0.2706) — an in-silico prediction, not a clinical call.

DCC p.Ile759Met

c.2277T>G · rs2278339 · VCV3042915

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2706 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.66%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DCC-related disorder

Computational evidence

Protein change
AlphaMissense	0.2706	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -5.1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	18.34	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 2.66% East Asian · 1,193/44,870 alleles

Filtering AF 2.53% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.48%

Overall 0.0839% 1,354/1,614,034 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	2.66%	38
South Asian	0.12%	836
Remaining individualsnot grpmax-eligible	0.0352%	2,841
European (non-Finnish)	0.00246%	40,688
Admixed American	0.00167%	59,974

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.Ile759Met
Coding: c.2277T>G
MANE Select: NM_005215
dbSNP: rs2278339
Type: single nucleotide variant
Location: chr18:53339825 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 759: a β-strand; the fibronectin type-iii 4 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic); a UniProt-annotated variant site (in)

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-ile759met (accessed [today's date]).

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