Is DRC1 p.Val633Phe (c.1897G>T) pathogenic?

DRC1 p.Val633Phe (c.1897G>T) is classified Benign/Likely benign in DRC1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.4773); Common (popmax 61.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with primary ciliary dyskinesia.

What condition is associated with DRC1 p.Val633Phe (c.1897G>T)?

DRC1 p.Val633Phe (c.1897G>T) is associated with primary ciliary dyskinesia (ClinVar).

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.Val633Phe (c.1897G>T)?

AlphaMissense predicts ambiguous (score 0.4773) — an in-silico prediction, not a clinical call.

DRC1 p.Val633Phe

Q: How common is DRC1 p.Val633Phe (c.1897G>T) in the general population?

DRC1 p.Val633Phe (c.1897G>T) is common (popmax 61.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1897G>T · rs12623642 · VCV402798

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4773 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 61.2%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.4773	ambiguous
REVEL	0.185	benign-leaning
SaProt	LLR -5.53	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 55 kb · p 0.71 · regional, not allelic
Overall
CADD	23.8	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 61.2% East Asian · 27,460/44,842 alleles

Filtering AF 60.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 60.4%

Overall 9.18% 148,132/1,613,792 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	61.2%	2
Admixed American	31.1%	3
Remaining individualsnot grpmax-eligible	9.99%	10
South Asian	9.73%	10
Ashkenazi Jewishnot grpmax-eligible	9.01%	11
Amishnot grpmax-eligible	8.44%	12
European (non-Finnish)	6.63%	15
Middle Eastern	5.25%	19
Finnishnot grpmax-eligible	5.18%	19
African / African-American	3.11%	32

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.Val633Phe
Coding: c.1897G>T
MANE Select: NM_145038
dbSNP: rs12623642
Type: single nucleotide variant
Location: chr2:26453527 (GRCh38)
Gene constraint: LOEUF 0.867 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.44 · 1 PDB
Residue 633: 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); a UniProt-annotated variant site (in spgf80); a UniProt-annotated variant site (in cild21)

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.Val633Ile Uncertain significance ★ ⚠ 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
DRC1 p.Ala416Gly Uncertain significance ★★ ⚠ same condition
DRC1 p.Ala45Val 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-val633phe (accessed [today's date]).

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