Is DRC1 p.Val690Ala (c.2069T>C) pathogenic?

DRC1 p.Val690Ala (c.2069T>C) is classified Conflicting classifications of pathogenicity in DRC1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-23). AlphaMissense: ambiguous (0.3565); Rare (popmax 0.367%, sas); Associated with primary ciliary dyskinesia.

What condition is associated with DRC1 p.Val690Ala (c.2069T>C)?

DRC1 p.Val690Ala (c.2069T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is DRC1 p.Val690Ala (c.2069T>C) in the general population?

DRC1 p.Val690Ala (c.2069T>C) is rare (popmax 0.367%, sas) (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.Val690Ala (c.2069T>C)?

AlphaMissense predicts ambiguous (score 0.3565) — an in-silico prediction, not a clinical call.

DRC1 p.Val690Ala

c.2069T>C · rs199858918 · VCV1625444

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3565 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.367%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.3565	ambiguous
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.92	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 55 kb · p 0.71 · regional, not allelic
Overall
CADD	22.8	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 0.367% South Asian · 334/91,070 alleles

Filtering AF 0.334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.322%

Overall 0.0226% 365/1,614,034 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.367%	273
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Middle Eastern	0.033%	3,031
Admixed American	0.00333%	30,002
European (non-Finnish)	0.000424%	236,001

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.Val690Ala
Coding: c.2069T>C
MANE Select: NM_145038
dbSNP: rs199858918
Type: single nucleotide variant
Location: chr2:26455136 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.44 · 1 PDB
Residue 690: a UniProt-annotated variant site (in cild21; multiple flagellar abnormalities are present in patient sperm); a UniProt-annotated variant site (in spgf80; no protein detected in a homozygous patient sperm); a UniProt-annotated variant site (in cild21); a UniProt-annotated variant site (in spgf80)

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.Val690= Benign/Likely benign ★★ same residue
DRC1 p.Val690Ile Uncertain significance ★ ⚠ same residue
DRC1 p.Val690fs Pathogenic ★★ 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

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-val690ala (accessed [today's date]).

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