Is DRC1 p.Ala474Thr (c.1420G>A) pathogenic?

DRC1 p.Ala474Thr (c.1420G>A) is classified Conflicting classifications of pathogenicity in DRC1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-09-24). AlphaMissense: likely benign (0.0712); Rare (popmax 0.116%, afr); Associated with primary ciliary dyskinesia.

What condition is associated with DRC1 p.Ala474Thr (c.1420G>A)?

DRC1 p.Ala474Thr (c.1420G>A) is associated with primary ciliary dyskinesia (ClinVar).

How common is DRC1 p.Ala474Thr (c.1420G>A) in the general population?

DRC1 p.Ala474Thr (c.1420G>A) is rare (popmax 0.116%, afr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DRC1 p.Ala474Thr (c.1420G>A)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

DRC1 p.Ala474Thr

c.1420G>A · rs145706376 · VCV663118

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.2
Regional constraint	o/e 0.99	unconstrained · MANE · 55 kb · p 0.71 · regional, not allelic
Overall
CADD	0.024	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 0.116% African / African-American · 87/75,052 alleles

Filtering AF 0.0963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0889%

Overall 0.00706% 114/1,614,184 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.116%	863
Admixed American	0.005%	20,011
Remaining individualsnot grpmax-eligible	0.0048%	20,834
South Asian	0.0022%	45,542
European (non-Finnish)	0.00161%	62,107

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: DRC1
Protein: p.Ala474Thr
Coding: c.1420G>A
MANE Select: NM_145038
dbSNP: rs145706376
Type: single nucleotide variant
Location: chr2:26448714 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.44 · 1 PDB
Residue 474: a UniProt-annotated variant site (in cild21; multiple flagellar abnormalities are present in patient sperm); 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

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

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

DRC1 p.Ala474= Likely benign ★ same residue
DRC1 p.Gln118Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Gln337Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Ser642Ter Pathogenic/Likely pathogenic ★★ same condition
DRC1 p.Ala250Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala391Val Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala416Gly Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala45Val 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-ala474thr (accessed [today's date]).

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