Is CFAP418 p.Arg131Cys (c.391C>T) pathogenic?

CFAP418 p.Arg131Cys (c.391C>T) is classified Uncertain significance in CFAP418 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-13). AlphaMissense: ambiguous (0.3655); Very rare (popmax 0.00127%, nfe).

How common is CFAP418 p.Arg131Cys (c.391C>T) in the general population?

CFAP418 p.Arg131Cys (c.391C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about CFAP418 p.Arg131Cys (c.391C>T)?

AlphaMissense predicts ambiguous (score 0.3655) — an in-silico prediction, not a clinical call.

CFAP418 p.Arg131Cys

c.391C>T · rs752701566 · VCV1681124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3655	ambiguous
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -13.94	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.25	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.91 · regional, not allelic
Overall
CADD	33.0	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 0.00127% European (non-Finnish) · 15/1,179,202 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.0011% 16/1,460,736 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)grpmax	0.00127%	78,613

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: CFAP418
Protein: p.Arg131Cys
Coding: c.391C>T
MANE Select: NM_177965
dbSNP: rs752701566
Type: single nucleotide variant
Location: chr8:95252267 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.73

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

Similar variants

CFAP418 p.Arg131His 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
CFAP418 p.Ala178Val Uncertain significance ★★ ⚠ same type
CFAP418 p.Ala45Gly 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-arg131cys (accessed [today's date]).

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