Is DCC p.Val754Met (c.2260G>A) pathogenic?

DCC p.Val754Met (c.2260G>A) is classified Uncertain significance in DCC (ClinVar, Single submitter, 3 submitters; last evaluated 2023-10-13). AlphaMissense: likely benign (0.2891); Rare (popmax 0.136%, eas); Associated with autism spectrum disorder.

What condition is associated with DCC p.Val754Met (c.2260G>A)?

DCC p.Val754Met (c.2260G>A) is associated with autism spectrum disorder, corpus callosum, agenesis of (ClinVar).

How common is DCC p.Val754Met (c.2260G>A) in the general population?

DCC p.Val754Met (c.2260G>A) is rare (popmax 0.136%, eas) (gnomAD).

What do computational predictors say about DCC p.Val754Met (c.2260G>A)?

AlphaMissense predicts likely benign (score 0.2891) — an in-silico prediction, not a clinical call.

DCC p.Val754Met

c.2260G>A · rs775565634 · VCV375286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2891 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autism spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.2891	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -7.41	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.136% East Asian · 61/44,868 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0987%

Overall 0.00465% 75/1,613,878 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.136%	736
Remaining individualsnot grpmax-eligible	0.0048%	20,831
South Asian	0.0011%	91,082
European (non-Finnish)	0.000848%	117,993

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.Val754Met
Coding: c.2260G>A
MANE Select: NM_005215
dbSNP: rs775565634
Type: single nucleotide variant
Location: chr18:53339808 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 754: the fibronectin type-iii 4 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic); a UniProt-annotated variant site (in mrmv1; uncertain significance)

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

Disease context

autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: corpus callosum, agenesis of

Similar variants

DCC p.Arg275Ter Pathogenic ★★ same condition
DCC p.Asp206Val Likely pathogenic ★ same condition
DCC p.Met743Leu Uncertain significance ★ ⚠ same condition
DCC p.Ala893Thr Pathogenic ⚠ same condition
DCC p.Arg597Pro Pathogenic same condition
DCC p.Gly805Glu Pathogenic same condition
DCC p.Val793Gly Pathogenic same condition
DCC p.Thr309fs Pathogenic 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-val754met (accessed [today's date]).

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