Is CFAP43 p.Trp141Arg (c.421T>A) pathogenic?

CFAP43 p.Trp141Arg (c.421T>A) is classified Uncertain significance in CFAP43 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely pathogenic (0.9868); Very rare (popmax 0.00026%, nfe); Associated with spermatogenic failure 19.

What condition is associated with CFAP43 p.Trp141Arg (c.421T>A)?

CFAP43 p.Trp141Arg (c.421T>A) is associated with spermatogenic failure 19 (ClinVar).

How common is CFAP43 p.Trp141Arg (c.421T>A) in the general population?

CFAP43 p.Trp141Arg (c.421T>A) is very rare (popmax 0.00026%, nfe) (gnomAD).

What do computational predictors say about CFAP43 p.Trp141Arg (c.421T>A)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

CFAP43 p.Trp141Arg

c.421T>A · rs367559937 · VCV3778881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00026%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spermatogenic failure 19

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic · top 1% in CFAP43
REVEL	0.559	indeterminate
SaProt	LLR -11.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.88	acceptor gain · deltas
Pangolin	Δ0.25	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 91 kb · p 0.0013 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00026% European (non-Finnish) · 3/1,154,936 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000212% 3/1,416,700 alleles · very rare

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: CFAP43
Protein: p.Trp141Arg
Coding: c.421T>A
MANE Select: NM_025145
dbSNP: rs367559937
Type: single nucleotide variant
Location: chr10:104214422 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.27 · 1 PDB

Full CFAP43 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 19 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFAP43 p.Arg894Ter Pathogenic/Likely pathogenic ★★ same condition
CFAP43 p.Arg1049Ter Likely pathogenic ★ same condition
CFAP43 p.Glu920Ter Likely pathogenic ★ same condition
CFAP43 p.Val310Ala Conflicting classifications of pathogenicity ★ ⚠ same condition
CFAP43 c.3541-2A>C Pathogenic same condition
CFAP43 p.Arg1118Ter Pathogenic same condition
CFAP43 p.Arg1378Ter Pathogenic same condition
CFAP43 p.Arg85Trp Pathogenic ⚠ 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/cfap43-p-trp141arg (accessed [today's date]).

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