Is DCC p.Arg386Gln (c.1157G>A) pathogenic?

DCC p.Arg386Gln (c.1157G>A) is classified Conflicting classifications of pathogenicity in DCC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-06). AlphaMissense: likely benign (0.1749); Rare (popmax 0.347%, mid).

How common is DCC p.Arg386Gln (c.1157G>A) in the general population?

DCC p.Arg386Gln (c.1157G>A) is rare (popmax 0.347%, mid) (gnomAD).

What do computational predictors say about DCC p.Arg386Gln (c.1157G>A)?

AlphaMissense predicts likely benign (score 0.1749) — an in-silico prediction, not a clinical call.

DCC p.Arg386Gln

c.1157G>A · rs140711456 · VCV727883

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1749 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.347%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1749	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -8.14	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 9.8	GERP 0.32, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	23.5	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 0.347% Middle Eastern · 21/6,056 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0193% 312/1,613,026 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.347%	288
Ashkenazi Jewishnot grpmax-eligible	0.0778%	1,285
Remaining individualsnot grpmax-eligible	0.0688%	1,452
Admixed American	0.0284%	3,524
South Asian	0.022%	4,553
European (non-Finnish)	0.0146%	6,857
African / African-American	0.0134%	7,487
Finnishnot grpmax-eligible	0.00782%	12,788
East Asian	0.00223%	44,814

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.Arg386Gln
Coding: c.1157G>A
MANE Select: NM_005215
dbSNP: rs140711456
Type: single nucleotide variant
Location: chr18:53066062 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 386: 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

Similar variants

DCC p.Arg386Gly Uncertain significance ★ ⚠ same residue
DCC p.Arg1021Ter Pathogenic ★★ same type
DCC p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same type
DCC p.Arg275Ter Pathogenic ★★ same type
DCC p.Arg879Ter Pathogenic/Likely pathogenic ★★ same type
DCC c.3620-2A>G Uncertain significance ★★ same type
DCC p.Arg597Gln Uncertain significance ★★ ⚠ same type
DCC p.Gly1294Arg Uncertain significance ★★ ⚠ same type

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-arg386gln (accessed [today's date]).

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