Is AKTIP p.Met253Thr (c.758T>C) pathogenic?

AKTIP p.Met253Thr (c.758T>C) is classified Uncertain significance in AKTIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.9866); Absent from gnomAD v4.1.

How common is AKTIP p.Met253Thr (c.758T>C) in the general population?

AKTIP p.Met253Thr (c.758T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AKTIP p.Met253Thr (c.758T>C)?

AlphaMissense predicts likely pathogenic (score 0.9866) — an in-silico prediction, not a clinical call.

AKTIP p.Met253Thr

c.758T>C · VCV3519318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9866 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9866	likely pathogenic
REVEL	0.639	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,135 bp · p 0.26 · regional, not allelic
Overall
CADD	23.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AKTIP
Protein: p.Met253Thr
Coding: c.758T>C
MANE Select: NM_022476
Type: single nucleotide variant
Location: chr16:53492706 (GRCh38)
Gene constraint: LOEUF 0.612 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 1 PDB
Residue 253: an α-helix

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-met253thr (accessed [today's date]).

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