Is ARFIP2 p.Ser306Phe (c.917C>T) pathogenic?

ARFIP2 p.Ser306Phe (c.917C>T) is classified Uncertain significance in ARFIP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely pathogenic (0.8936); Ultra-rare (popmax 0.0183%, amr).

How common is ARFIP2 p.Ser306Phe (c.917C>T) in the general population?

ARFIP2 p.Ser306Phe (c.917C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ARFIP2 p.Ser306Phe (c.917C>T)?

AlphaMissense predicts likely pathogenic (score 0.8936) — an in-silico prediction, not a clinical call.

ARFIP2 p.Ser306Phe

c.917C>T · rs372336395 · VCV2400741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8936	likely pathogenic
REVEL	0.682	pathogenic-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 736 bp · p 0.57 · 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 0.0183% Admixed American · 11/59,960 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00737% 119/1,613,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,451
European (non-Finnish)	0.00907%	11,027
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: ARFIP2
Protein: p.Ser306Phe
Coding: c.917C>T
MANE Select: NM_001376558
dbSNP: rs372336395
Type: single nucleotide variant
Location: chr11:6477222 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 81.84 · 5 PDB
Residue 306: the ah domain; an α-helix

Full ARFIP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARFIP2 c.197-16G>A Uncertain significance ★ same type
ARFIP2 c.197-75G>A Uncertain significance ★ same type
ARFIP2 c.197-76A>G Uncertain significance ★ same type
ARFIP2 c.197-87C>T Uncertain significance ★ same type
ARFIP2 p.Ala252Ser Uncertain significance ★ ⚠ same type
ARFIP2 p.Arg138His Uncertain significance ★ ⚠ same type
ARFIP2 p.Arg148Gln Uncertain significance ★ ⚠ same type
ARFIP2 p.Arg269Trp 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/arfip2-p-ser306phe (accessed [today's date]).

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