Is ACIN1 p.Ser455Pro (c.1363T>C) pathogenic?

ACIN1 p.Ser455Pro (c.1363T>C) is classified Uncertain significance in ACIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely benign (0.0697); Very rare (popmax 0.000254%, nfe).

How common is ACIN1 p.Ser455Pro (c.1363T>C) in the general population?

ACIN1 p.Ser455Pro (c.1363T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ACIN1 p.Ser455Pro (c.1363T>C)?

AlphaMissense predicts likely benign (score 0.0697) — an in-silico prediction, not a clinical call.

ACIN1 p.Ser455Pro

c.1363T>C · VCV3998385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0697	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -5.95	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 1.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 21 kb · p 0.37 · regional, not allelic
Overall
CADD	16.22	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S513P vs ClinVar S455P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,044 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,974 alleles · very rare

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: ACIN1
Protein: p.Ser455Pro
Coding: c.1363T>C
MANE Select: NM_001386863
Type: single nucleotide variant
Location: chr14:23079972 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.21 · 1 PDB
Residue 455: the 'disordered' region

Full ACIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ACIN1 p.Ala39Thr Uncertain significance ★ ⚠ same type
ACIN1 p.Ala502Val Uncertain significance ★ ⚠ same type
ACIN1 p.Ala557Val Uncertain significance ★ ⚠ same type
ACIN1 p.Ala735Val Uncertain significance ★ ⚠ same type
ACIN1 p.Ala824Val 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/acin1-p-ser455pro (accessed [today's date]).

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