Is ACIN1 p.Pro508Ser (c.1522C>T) pathogenic?

ACIN1 p.Pro508Ser (c.1522C>T) is classified Uncertain significance in ACIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.1255); Rare (popmax 0.174%, eas).

How common is ACIN1 p.Pro508Ser (c.1522C>T) in the general population?

ACIN1 p.Pro508Ser (c.1522C>T) is rare (popmax 0.174%, eas) (gnomAD).

What do computational predictors say about ACIN1 p.Pro508Ser (c.1522C>T)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

ACIN1 p.Pro508Ser

c.1522C>T · rs115370646 · VCV2372651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.174%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -6.08	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 3	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 21 kb · p 0.37 · regional, not allelic
Overall
CADD	19.27	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 P566S vs ClinVar P508S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.174% East Asian · 78/44,888 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.131%

Overall 0.00675% 109/1,614,182 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.174%	575
Remaining individualsnot grpmax-eligible	0.032%	3,125
Middle Eastern	0.0165%	6,062
African / African-American	0.012%	8,336
South Asian	0.0011%	91,080

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.Pro508Ser
Coding: c.1522C>T
MANE Select: NM_001386863
dbSNP: rs115370646
Type: single nucleotide variant
Location: chr14:23079813 (GRCh38)
Gene constraint: LOEUF 0.15 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.21 · 1 PDB
Residue 508: 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-pro508ser (accessed [today's date]).

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