Is DRC4 p.Val97Met (c.289G>A) pathogenic?

DRC4 p.Val97Met (c.289G>A) is classified Uncertain significance in DRC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-31). AlphaMissense: likely pathogenic (0.6159); Ultra-rare (popmax 0.014%, nfe); Associated with primary ciliary dyskinesia 33.

What condition is associated with DRC4 p.Val97Met (c.289G>A)?

DRC4 p.Val97Met (c.289G>A) is associated with primary ciliary dyskinesia 33 (ClinVar).

How common is DRC4 p.Val97Met (c.289G>A) in the general population?

DRC4 p.Val97Met (c.289G>A) is ultra-rare (popmax 0.014%, nfe) (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.Val97Met (c.289G>A)?

AlphaMissense predicts likely pathogenic (score 0.6159) — an in-silico prediction, not a clinical call.

DRC4 p.Val97Met

c.289G>A · rs147133929 · VCV835829

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 33

Computational evidence

Protein change
AlphaMissense	0.6159	likely pathogenic
REVEL	0.21	benign-leaning
SaProt	LLR -6.34	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	33.0	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 0.014% European (non-Finnish) · 165/1,179,834 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0177% 286/1,613,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.156%	640
Remaining individualsnot grpmax-eligible	0.0336%	2,975
European (non-Finnish)grpmax	0.014%	7,151

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val97Met
Coding: c.289G>A
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.Val97Leu 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-val97met (accessed [today's date]).

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