Is DRC4 p.Val159Glu (c.476T>A) pathogenic?

DRC4 p.Val159Glu (c.476T>A) is classified Benign in DRC4 (ClinVar, Single submitter, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1615); Low-frequency (popmax 1.64%, afr); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Val159Glu (c.476T>A)?

DRC4 p.Val159Glu (c.476T>A) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Val159Glu (c.476T>A) in the general population?

DRC4 p.Val159Glu (c.476T>A) is low-frequency (popmax 1.64%, 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.Val159Glu (c.476T>A)?

AlphaMissense predicts likely benign (score 0.1615) — an in-silico prediction, not a clinical call.

DRC4 p.Val159Glu

c.476T>A · rs116113385 · VCV475565

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1615 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.1615	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -2.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	20.9	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 1.64% African / African-American · 1,228/74,884 alleles

Filtering AF 1.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 0.0856% 1,381/1,613,424 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.64%	61
Remaining individualsnot grpmax-eligible	0.109%	919
Admixed American	0.109%	921
Middle Eastern	0.0495%	2,020
European (non-Finnish)	0.00144%	69,397

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.Val159Glu
Coding: c.476T>A
MANE Select: NM_001481
dbSNP: rs116113385
Type: single nucleotide variant
Location: chr16:90032905 (GRCh38)
Structure: AlphaFold pLDDT 85.12 · 1 PDB
Residue 159: the '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.Val159Leu 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-val159glu (accessed [today's date]).

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