Is DRC4 p.Ala270Pro (c.808G>C) pathogenic?

DRC4 p.Ala270Pro (c.808G>C) is classified Conflicting classifications of pathogenicity in DRC4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.5317); Rare (popmax 0.36%, sas); Associated with Inborn genetic diseases.

What condition is associated with DRC4 p.Ala270Pro (c.808G>C)?

DRC4 p.Ala270Pro (c.808G>C) is associated with Inborn genetic diseases, primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Ala270Pro (c.808G>C) in the general population?

DRC4 p.Ala270Pro (c.808G>C) is rare (popmax 0.36%, sas) (gnomAD).

What do computational predictors say about DRC4 p.Ala270Pro (c.808G>C)?

AlphaMissense predicts ambiguous (score 0.5317) — an in-silico prediction, not a clinical call.

DRC4 p.Ala270Pro

c.808G>C · rs141125763 · VCV475568

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5317 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.36%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5317	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	phastCons 0.005
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	19.81	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 0.36% South Asian · 328/91,004 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.316%

Overall 0.188% 3,041/1,613,844 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.36%	277
Finnishnot grpmax-eligible	0.289%	346
European (non-Finnish)	0.198%	506
Remaining individualsnot grpmax-eligible	0.147%	679
Admixed American	0.12%	833
African / African-American	0.04%	2,502
Middle Eastern	0.0166%	6,014
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

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.Ala270Pro
Coding: c.808G>C
MANE Select: NM_001481
dbSNP: rs141125763
Type: single nucleotide variant
Location: chr16:90037283 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 270: a UniProt-annotated variant site (in cild33; loss of localization to cilia; abnormal cilia with axonemal disorganization)

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

Also linked: primary ciliary dyskinesia 33

Similar variants

DRC4 p.Ala270Val Uncertain significance ★ ⚠ same residue
DRC4 c.495+1G>T Likely pathogenic ★★ same condition
DRC4 p.Gln357Ter Pathogenic ★★ same condition
DRC4 p.Ala280Thr Uncertain significance ★★ ⚠ same condition
DRC4 p.Ala460Pro Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg143Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg164Trp Uncertain significance ★★ ⚠ same condition
DRC4 p.Arg203Gln 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-ala270pro (accessed [today's date]).

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