Is CFAP418 p.Ser65Ile (c.194G>T) pathogenic?

CFAP418 p.Ser65Ile (c.194G>T) is classified Uncertain significance in CFAP418 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1265); Ultra-rare (popmax 0.0267%, amr); Associated with cone-rod dystrophy 16.

What condition is associated with CFAP418 p.Ser65Ile (c.194G>T)?

CFAP418 p.Ser65Ile (c.194G>T) is associated with cone-rod dystrophy 16, retinitis pigmentosa, bardet-biedl syndrome 21 (ClinVar).

How common is CFAP418 p.Ser65Ile (c.194G>T) in the general population?

CFAP418 p.Ser65Ile (c.194G>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFAP418 p.Ser65Ile (c.194G>T)?

AlphaMissense predicts likely benign (score 0.1265) — an in-silico prediction, not a clinical call.

CFAP418 p.Ser65Ile

c.194G>T · rs969339085 · VCV957321

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1265 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 16

Computational evidence

Protein change
AlphaMissense	0.1265	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -0.078, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.91 · regional, not allelic
Overall
CADD	18.69	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 0.0267% Admixed American · 16/59,908 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00137% 22/1,609,258 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,744
Remaining individualsnot grpmax-eligible	0.00802%	12,463
African / African-American	0.00134%	74,812

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.Ser65Ile
Coding: c.194G>T
MANE Select: NM_177965
dbSNP: rs969339085
Type: single nucleotide variant
Location: chr8:95263736 (GRCh38)
Gene constraint: LOEUF 1.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.73
Residue 65: the 'required for interaction with fam161a' region

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

Disease context

cone-rod dystrophy 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa bardet-biedl syndrome 21

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CFAP418 p.Ser65= Likely benign same residue
CFAP418 p.Arg177Trp Pathogenic/Likely pathogenic ★★ same condition
CFAP418 p.Trp147Ter Pathogenic/Likely pathogenic ★★ same condition
CFAP418 c.*408G>A Uncertain significance ★★ same condition
CFAP418 c.*965C>G Uncertain significance ★★ same condition
CFAP418 p.Ala178Val Uncertain significance ★★ ⚠ same condition
CFAP418 p.Ala45Gly Uncertain significance ★★ ⚠ same condition
CFAP418 p.Arg177Gln Uncertain significance ★★ ⚠ 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/cfap418-p-ser65ile (accessed [today's date]).

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