Is DRC1 p.Arg219Ser (c.655C>A) pathogenic?

DRC1 p.Arg219Ser (c.655C>A) is classified Uncertain significance in DRC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: ambiguous (0.5197); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DRC1 p.Arg219Ser (c.655C>A)?

DRC1 p.Arg219Ser (c.655C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DRC1 p.Arg219Ser (c.655C>A) in the general population?

DRC1 p.Arg219Ser (c.655C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DRC1 p.Arg219Ser (c.655C>A)?

AlphaMissense predicts ambiguous (score 0.5197) — an in-silico prediction, not a clinical call.

DRC1 p.Arg219Ser

c.655C>A · rs577516330 · VCV2235364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5197 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5197	ambiguous
REVEL	0.193	benign-leaning
SaProt	LLR -9.26	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.31	donor gain · deltas
Pangolin	Δ0.23	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 55 kb · p 0.71 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DRC1
Protein: p.Arg219Ser
Coding: c.655C>A
MANE Select: NM_145038
dbSNP: rs577516330
Type: single nucleotide variant
Location: chr2:26429742 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.44 · 1 PDB
Residue 219: a UniProt-annotated variant site (in spgf80); a UniProt-annotated variant site (in cild21)

Full DRC1 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

DRC1 p.Arg219His Uncertain significance ★ ⚠ same residue
DRC1 p.Arg219Leu Uncertain significance ★ ⚠ same residue
DRC1 p.Arg219Cys Likely benign ★★ ⚠ same residue
DRC1 p.Ala250Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala391Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala45Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala473Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Arg206Gln 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/drc1-p-arg219ser (accessed [today's date]).

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