Is DCC p.Gly556Ser (c.1666G>A) pathogenic?

DCC p.Gly556Ser (c.1666G>A) is classified Uncertain significance in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: ambiguous (0.4191); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with DCC p.Gly556Ser (c.1666G>A)?

DCC p.Gly556Ser (c.1666G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DCC p.Gly556Ser (c.1666G>A) in the general population?

DCC p.Gly556Ser (c.1666G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about DCC p.Gly556Ser (c.1666G>A)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

DCC p.Gly556Ser

c.1666G>A · rs771834549 · VCV2375058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.419	indeterminate
SaProt	LLR -10.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	25.3	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000684% 10/1,461,688 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
African / African-American	0.00667%	14,996
East Asian	0.00223%	44,866
European (non-Finnish)	0.00017%	589,929

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.Gly556Ser
Coding: c.1666G>A
MANE Select: NM_005215
dbSNP: rs771834549
Type: single nucleotide variant
Location: chr18:53205308 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 556: the fibronectin type-iii 2 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DCC p.Arg1021Ter Pathogenic ★★ same condition
DCC p.Arg597Gln Uncertain significance ★★ ⚠ same condition
DCC p.Gly84Arg Uncertain significance ★★ ⚠ same condition
DCC p.Ile1080Val Uncertain significance ★★ ⚠ same condition
DCC p.Gln486Leu Benign ★★ ⚠ same condition
DCC p.Arg215Ter Pathogenic ★ same condition
DCC p.Gly556fs Likely pathogenic ★ same residue
DCC c.3392+4G>A 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-gly556ser (accessed [today's date]).

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