Is CFAP53 p.Val259= (c.777G>T) pathogenic?

CFAP53 p.Val259= (c.777G>T) is classified Likely pathogenic in CFAP53 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-24). Very rare (popmax 0.00445%, eas); Associated with Heterotaxy.

What condition is associated with CFAP53 p.Val259= (c.777G>T)?

CFAP53 p.Val259= (c.777G>T) is associated with Heterotaxy (ClinVar).

How common is CFAP53 p.Val259= (c.777G>T) in the general population?

CFAP53 p.Val259= (c.777G>T) is very rare (popmax 0.00445%, eas) (gnomAD).

CFAP53 p.Val259=

c.777G>T · rs557771609 · VCV1065355

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

Heterotaxy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.78	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 1
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00118% 19/1,611,440 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,602
East Asiangrpmax	0.00445%	22,449
South Asian	0.0022%	45,485
European (non-Finnish)	0.000933%	107,221

Remaining individuals 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: CFAP53
Protein: p.Val259=
Coding: c.777G>T
MANE Select: NM_145020
dbSNP: rs557771609
Type: single nucleotide variant
Location: chr18:50251481 (GRCh38)
Gene constraint: LOEUF 1.282 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.17 · 2 PDB
Residue 259: the trichohyalin-plectin-homology domain; a UniProt-annotated variant site (in htx6; uncertain significance; no overt effects on the structure or function of respiratory cilia)

Full CFAP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Heterotaxy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFAP53 p.Ala185Thr Uncertain significance ★★ ⚠ same type
CFAP53 p.Ala385Ser Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg158Gly Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg257Cys Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg470His Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg505His Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg505Leu Uncertain significance ★★ ⚠ same type
CFAP53 p.Arg505Ser Uncertain significance ★★ ⚠ same type

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/cfap53-p-val259 (accessed [today's date]).

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