Is DRC4 p.Val97Leu (c.289G>T) pathogenic?

DRC4 p.Val97Leu (c.289G>T) is classified Uncertain significance in DRC4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-29). AlphaMissense: likely pathogenic (0.711); Ultra-rare (popmax 0.0681%, afr); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Val97Leu (c.289G>T)?

DRC4 p.Val97Leu (c.289G>T) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Val97Leu (c.289G>T) in the general population?

DRC4 p.Val97Leu (c.289G>T) is ultra-rare (popmax 0.0681%, 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 DRC4 p.Val97Leu (c.289G>T)?

AlphaMissense predicts likely pathogenic (score 0.711) — an in-silico prediction, not a clinical call.

DRC4 p.Val97Leu

c.289G>T · rs147133929 · VCV849223

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.711 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.711	likely pathogenic · top 9% in DRC4
REVEL	0.147	moderately benign-leaning
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	28.7	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

Grpmax group 0.0681% African / African-American · 51/74,938 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00397% 64/1,613,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0681%	1,469
Admixed American	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	8.48e-05%	1,179,828

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.Val97Leu
Coding: c.289G>T
MANE Select: NM_001481
dbSNP: rs147133929
Type: single nucleotide variant
Location: chr16:90032718 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 97: the 'regulates microtubule-binding' region

Full DRC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 33 — 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

DRC4 p.Val97Met Uncertain significance ★★ same residue
DRC4 p.Val97Ala 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

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-val97leu (accessed [today's date]).

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