Is CFAP58 p.Leu519Ser (c.1556T>C) pathogenic?

CFAP58 p.Leu519Ser (c.1556T>C) is classified Uncertain significance in CFAP58 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: ambiguous (0.4064); Very rare (popmax 0.00223%, eas).

How common is CFAP58 p.Leu519Ser (c.1556T>C) in the general population?

CFAP58 p.Leu519Ser (c.1556T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CFAP58 p.Leu519Ser (c.1556T>C)?

AlphaMissense predicts ambiguous (score 0.4064) — an in-silico prediction, not a clinical call.

CFAP58 p.Leu519Ser

c.1556T>C · VCV3491373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.4064	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -11.34	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.33 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,836 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000509%	196,628

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: CFAP58
Protein: p.Leu519Ser
Coding: c.1556T>C
MANE Select: NM_001008723
Type: single nucleotide variant
Location: chr10:104393357 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.87 · 1 PDB

Full CFAP58 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP58 p.Thr783Met Uncertain significance ★★ ⚠ same type
CFAP58 p.Arg698Ter Pathogenic ★ same type
CFAP58 p.Gln454Ter Likely pathogenic ★ same type
CFAP58 c.2039+3A>G Uncertain significance ★ same type
CFAP58 p.Ala102Thr Uncertain significance ★ ⚠ same type
CFAP58 p.Ala177Pro Uncertain significance ★ ⚠ same type
CFAP58 p.Ala311Thr Uncertain significance ★ ⚠ same type
CFAP58 p.Ala311Val 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/cfap58-p-leu519ser (accessed [today's date]).

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