Is DCC p.Arg667His (c.2000G>A) pathogenic?

DCC p.Arg667His (c.2000G>A) is classified Benign/Likely benign in DCC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1751); Low-frequency (popmax 1.06%, mid).

How common is DCC p.Arg667His (c.2000G>A) in the general population?

DCC p.Arg667His (c.2000G>A) is low-frequency (popmax 1.06%, mid) (gnomAD).

What do computational predictors say about DCC p.Arg667His (c.2000G>A)?

AlphaMissense predicts likely benign (score 0.1751) — an in-silico prediction, not a clinical call.

DCC p.Arg667His

c.2000G>A · rs200099519 · VCV187791

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1751 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.06%, mid)

Conditions

Computational evidence

Protein change
AlphaMissense	0.1751	likely benign
REVEL	0.421	indeterminate
SaProt	—	withheld · numbering disagrees past residue 178 · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.06% Middle Eastern · 64/6,060 alleles

Filtering AF 0.849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.773%

Overall 0.0796% 1,284/1,613,934 alleles · low-frequency exomes 1,205/1,461,682 · genomes 79/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.06%	95
South Asian	0.842%	119
Remaining individualsnot grpmax-eligible	0.122%	822
Admixed American	0.0383%	2,609
European (non-Finnish)	0.0287%	3,480
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
African / African-American	0.008%	12,506
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00156%	64,020

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.Arg667His
Coding: c.2000G>A
MANE Select: NM_005215
dbSNP: rs200099519
Type: single nucleotide variant
Location: chr18:53305666 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 667: the fibronectin type-iii 3 domain; a UniProt-annotated variant site (in mrmv1; likely pathogenic); a β-strand

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

Disease context

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

Similar variants

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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
DCC c.91+7G>A 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-arg667his (accessed [today's date]).

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