Is DRC5 p.Arg133Pro (c.398G>C) pathogenic?

DRC5 p.Arg133Pro (c.398G>C) is classified Uncertain significance in DRC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely pathogenic (0.8017); Ultra-rare (popmax 0.0959%, afr).

How common is DRC5 p.Arg133Pro (c.398G>C) in the general population?

DRC5 p.Arg133Pro (c.398G>C) is ultra-rare (popmax 0.0959%, afr) (gnomAD).

What do computational predictors say about DRC5 p.Arg133Pro (c.398G>C)?

AlphaMissense predicts likely pathogenic (score 0.8017) — an in-silico prediction, not a clinical call.

DRC5 p.Arg133Pro

c.398G>C · rs151164597 · VCV2347785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8017 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0959%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8017	likely pathogenic · top 8% in DRC5
REVEL	0.716	pathogenic-leaning
SaProt	LLR -14.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,641 bp · p 0.39 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0959% African / African-American · 72/75,056 alleles

Filtering AF 0.0781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0715%

Overall 0.00632% 102/1,614,134 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0959%	1,042
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0128%	7,813
Admixed American	0.00833%	12,007
European (non-Finnish)	0.00136%	73,752

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: DRC5
Protein: p.Arg133Pro
Coding: c.398G>C
MANE Select: NM_182539
dbSNP: rs151164597
Type: single nucleotide variant
Location: chr6:44286412 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 1 PDB

Full DRC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRC5 p.Arg133His Uncertain significance ★ ⚠ same residue
DRC5 p.Ala351Asp Uncertain significance ★ ⚠ same type
DRC5 p.Ala381Thr Uncertain significance ★ ⚠ same type
DRC5 p.Ala385Gly Uncertain significance ★ ⚠ same type
DRC5 p.Arg158Gln Uncertain significance ★ ⚠ same type
DRC5 p.Arg185Gly Uncertain significance ★ ⚠ same type
DRC5 p.Arg185Trp Uncertain significance ★ ⚠ same type
DRC5 p.Arg207Gln 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/drc5-p-arg133pro (accessed [today's date]).

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