Is AKTIP p.Leu194Arg (c.581T>G) pathogenic?

AKTIP p.Leu194Arg (c.581T>G) is classified Uncertain significance in AKTIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.3249); Ultra-rare (popmax 0.0329%, mid).

How common is AKTIP p.Leu194Arg (c.581T>G) in the general population?

AKTIP p.Leu194Arg (c.581T>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about AKTIP p.Leu194Arg (c.581T>G)?

AlphaMissense predicts likely benign (score 0.3249) — an in-silico prediction, not a clinical call.

AKTIP p.Leu194Arg

c.581T>G · rs773241653 · VCV3108305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3249	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,135 bp · p 0.26 · regional, not allelic
Overall
CADD	27.8	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.0018% 29/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00195%	51,305
Admixed American	0.00167%	60,012
South Asian	0.0011%	91,090

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: AKTIP
Protein: p.Leu194Arg
Coding: c.581T>G
MANE Select: NM_022476
dbSNP: rs773241653
Type: single nucleotide variant
Location: chr16:53494360 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 1 PDB
Residue 194: the ubc core domain

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

Similar variants

AKTIP p.Ala235Thr Likely benign ★★ ⚠ same type
AKTIP p.Ala47Val Uncertain significance ★ ⚠ same type
AKTIP p.Arg101His Uncertain significance ★ ⚠ same type
AKTIP p.Arg101Ser Uncertain significance ★ ⚠ same type
AKTIP p.Arg113Gln Uncertain significance ★ ⚠ same type
AKTIP p.Arg139Cys Uncertain significance ★ ⚠ same type
AKTIP p.Arg13Cys Uncertain significance ★ ⚠ same type
AKTIP p.Asp205Gly 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/aktip-p-leu194arg (accessed [today's date]).

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