Is DRC4 p.Arg46Trp (c.136C>T) pathogenic?

DRC4 p.Arg46Trp (c.136C>T) is classified Uncertain significance in DRC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-03). AlphaMissense: ambiguous (0.4604); Ultra-rare (popmax 0.0178%, eas); Associated with Inborn genetic diseases.

What condition is associated with DRC4 p.Arg46Trp (c.136C>T)?

DRC4 p.Arg46Trp (c.136C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DRC4 p.Arg46Trp (c.136C>T) in the general population?

DRC4 p.Arg46Trp (c.136C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about DRC4 p.Arg46Trp (c.136C>T)?

AlphaMissense predicts ambiguous (score 0.4604) — an in-silico prediction, not a clinical call.

DRC4 p.Arg46Trp

c.136C>T · rs781653515 · VCV3098683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4604	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -13.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	33.0	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 0.0178% East Asian · 8/44,880 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00112% 18/1,613,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
Finnishnot grpmax-eligible	0.00157%	63,578
South Asian	0.0011%	91,076
European (non-Finnish)	0.000678%	147,486

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: DRC4
Protein: p.Arg46Trp
Coding: c.136C>T
MANE Select: NM_001481
dbSNP: rs781653515
Type: single nucleotide variant
Location: chr16:90031344 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 46: the 'regulates microtubule-binding' region

Full DRC4 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

DRC4 p.Arg46Leu Uncertain significance ★ ⚠ same residue
DRC4 p.Arg46Gln Uncertain significance ★ ⚠ same residue
DRC4 p.Ala280Thr Uncertain significance ★★ ⚠ same condition
DRC4 p.Ala460Pro Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg203Gln Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg278Cys Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg342Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg369Cys 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/drc4-p-arg46trp (accessed [today's date]).

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