Is CFAP418 p.Ser40Arg (c.120C>G) pathogenic?

CFAP418 p.Ser40Arg (c.120C>G) is classified Uncertain significance in CFAP418 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-17). AlphaMissense: likely benign (0.1218); Ultra-rare (popmax 0.0133%, amr).

How common is CFAP418 p.Ser40Arg (c.120C>G) in the general population?

CFAP418 p.Ser40Arg (c.120C>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CFAP418 p.Ser40Arg (c.120C>G)?

AlphaMissense predicts likely benign (score 0.1218) — an in-silico prediction, not a clinical call.

CFAP418 p.Ser40Arg

c.120C>G · rs1262940228 · VCV1681148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1218	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 0.53, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.91 · regional, not allelic
Overall
CADD	15.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0133% Admixed American · 8/60,018 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00347% 56/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,502
European (non-Finnish)	0.0039%	25,652
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,938

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: CFAP418
Protein: p.Ser40Arg
Coding: c.120C>G
MANE Select: NM_177965
dbSNP: rs1262940228
Type: single nucleotide variant
Location: chr8:95269070 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 40: the 'required for interaction with fam161a' region; the 'disordered' region

Full CFAP418 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP418 p.Ser40Gly Uncertain significance ★ ⚠ same residue
CFAP418 p.Ser40Thr Uncertain significance ★ ⚠ same residue
CFAP418 p.Ser40= Likely benign same residue
CFAP418 p.Arg177Trp Pathogenic/Likely pathogenic ★★ same type
CFAP418 p.Trp147Ter Pathogenic/Likely pathogenic ★★ same type
CFAP418 p.Trp185Ter Pathogenic/Likely pathogenic ★★ same type
CFAP418 c.*408G>A Uncertain significance ★★ same type
CFAP418 c.*965C>G 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/cfap418-p-ser40arg (accessed [today's date]).

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