Is DCC p.Pro373Ser (c.1117C>T) pathogenic?

DCC p.Pro373Ser (c.1117C>T) is classified Uncertain significance in DCC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: ambiguous (0.3894); Very rare (popmax 0.000849%, nfe).

How common is DCC p.Pro373Ser (c.1117C>T) in the general population?

DCC p.Pro373Ser (c.1117C>T) is very rare (popmax 0.000849%, nfe) (gnomAD).

What do computational predictors say about DCC p.Pro373Ser (c.1117C>T)?

AlphaMissense predicts ambiguous (score 0.3894) — an in-silico prediction, not a clinical call.

DCC p.Pro373Ser

c.1117C>T · rs925711337 · VCV2446590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000849%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3894	ambiguous
REVEL	0.441	indeterminate
SaProt	LLR -7.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,190 kb · p 0.4 · regional, not allelic
Overall
CADD	24.9	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 0.000849% European (non-Finnish) · 10/1,177,188 alleles

Filtering AF 0.00043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000686% 10/1,458,562 alleles · very rare

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.Pro373Ser
Coding: c.1117C>T
MANE Select: NM_005215
dbSNP: rs925711337
Type: single nucleotide variant
Location: chr18:53063436 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.60 · 9 PDB
Residue 373: 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.Pro373Arg 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-pro373ser (accessed [today's date]).

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