Is DCC p.Val354= (c.1062C>T) pathogenic?

DCC p.Val354= (c.1062C>T) is classified Benign/Likely benign in DCC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-01). Low-frequency (popmax 2.81%, mid); Associated with esophageal cancer.

What condition is associated with DCC p.Val354= (c.1062C>T)?

DCC p.Val354= (c.1062C>T) is associated with esophageal cancer, colorectal cancer, gaze palsy, familial horizontal, with progressive scoliosis, 2 (ClinVar).

How common is DCC p.Val354= (c.1062C>T) in the general population?

DCC p.Val354= (c.1062C>T) is low-frequency (popmax 2.81%, mid) (gnomAD).

DCC p.Val354=

c.1062C>T · rs141716650 · VCV773345

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.81%, mid)

Conditions

esophageal cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP -0.82, phastCons 0.59
Overall
CADD	6.019	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.81% Middle Eastern · 170/6,052 alleles

Filtering AF 2.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.33%

Overall 0.601% 9,692/1,612,536 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.81%	36
Finnishnot grpmax-eligible	1.94%	52
South Asian	1.36%	73
Remaining individualsnot grpmax-eligible	0.781%	128
Ashkenazi Jewishnot grpmax-eligible	0.602%	166
European (non-Finnish)	0.493%	203
Admixed American	0.45%	222
East Asian	0.435%	230
African / African-American	0.133%	749

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.Val354=
Coding: c.1062C>T
MANE Select: NM_005215
dbSNP: rs141716650
Type: single nucleotide variant
Location: chr18:53063381 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 354: a disulfide bond; a UniProt-annotated variant site (in mrmv1; likely pathogenic); the ig-like c2-type 4 domain

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

Disease context

esophageal cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer gaze palsy, familial horizontal, with progressive scoliosis, 2

Similar variants

DCC p.Val354Ile Uncertain significance ★ ⚠ same residue
DCC p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same condition
DCC p.Arg275Ter Pathogenic ★★ same condition
DCC p.Arg879Ter Pathogenic/Likely pathogenic ★★ same condition
DCC p.Gly803Arg Uncertain significance ★★ ⚠ same condition
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

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-val354 (accessed [today's date]).

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