Is ANKFN1 p.Arg412Cys (c.1234C>T) pathogenic?

ANKFN1 p.Arg412Cys (c.1234C>T) is classified Uncertain significance in ANKFN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.6051); Ultra-rare (popmax 0.0283%, amr).

How common is ANKFN1 p.Arg412Cys (c.1234C>T) in the general population?

ANKFN1 p.Arg412Cys (c.1234C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about ANKFN1 p.Arg412Cys (c.1234C>T)?

AlphaMissense predicts likely pathogenic (score 0.6051) — an in-silico prediction, not a clinical call.

ANKFN1 p.Arg412Cys

c.1234C>T · VCV3541908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Computational evidence

Protein change
AlphaMissense	0.6051	likely pathogenic
REVEL	0.307	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.8, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 299 kb · p 0.00097 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R415C vs ClinVar R412C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 17/59,996 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0026% 42/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,529
East Asian	0.00891%	11,220
European (non-Finnish)	0.00161%	62,104
Remaining individualsnot grpmax-eligible	0.0016%	62,482
South Asian	0.0011%	91,072

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: ANKFN1
Protein: p.Arg412Cys
Coding: c.1234C>T
MANE Select: NM_001370326
Type: single nucleotide variant
Location: chr17:56456887 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.55

Full ANKFN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKFN1 p.Arg412His Uncertain significance ★ ⚠ same residue
ANKFN1 p.Arg412Ser Uncertain significance ★ ⚠ same residue
ANKFN1 c.2260+19C>T Uncertain significance ★ ⚠ same type
ANKFN1 c.-73A>G Uncertain significance ★ ⚠ same type
ANKFN1 c.-88G>C Uncertain significance ★ ⚠ same type
ANKFN1 p.Ala24Thr Uncertain significance ★ ⚠ same type
ANKFN1 p.Ala267Val Uncertain significance ★ ⚠ same type
ANKFN1 p.Ala346Ser 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/ankfn1-p-arg412cys (accessed [today's date]).

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