Is ATN1 p.Pro720Ser (c.2158C>T) pathogenic?

ATN1 p.Pro720Ser (c.2158C>T) is classified Uncertain significance in ATN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.00196%, amr); Associated with Inborn genetic diseases.

What condition is associated with ATN1 p.Pro720Ser (c.2158C>T)?

ATN1 p.Pro720Ser (c.2158C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ATN1 p.Pro720Ser (c.2158C>T) in the general population?

ATN1 p.Pro720Ser (c.2158C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about ATN1 p.Pro720Ser (c.2158C>T)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

ATN1 p.Pro720Ser

c.2158C>T · rs781828877 · VCV2230501

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.81	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 1.2	GERP -1.8, phastCons 0.65
Regional constraint	o/e 1.08	unconstrained · MANE · 2,792 bp · p 0.013 · regional, not allelic
Overall
CADD	20.8	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 0.00196% Admixed American · 1/51,096 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000321%

Overall 0.00103% 16/1,547,500 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.005%	20,013
Admixed Americangrpmax	0.00196%	51,096
African / African-American	0.00137%	73,164
South Asian	0.00119%	84,348
European (non-Finnish)	0.000872%	114,737

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ATN1
Protein: p.Pro720Ser
Coding: c.2158C>T
MANE Select: NM_001940
dbSNP: rs781828877
Type: single nucleotide variant
Location: chr12:6937425 (GRCh38)
Gene constraint: LOEUF 0.352 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.25
Residue 720: the 'disordered' region

Full ATN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATN1 p.Arg1152Cys Uncertain significance ★★ ⚠ same condition
ATN1 p.Asn422Ser Uncertain significance ★★ ⚠ same condition
ATN1 p.Glu814Gly Uncertain significance ★★ ⚠ same condition
ATN1 p.Met335Ile Uncertain significance ★★ ⚠ same condition
ATN1 p.Pro185Ala Uncertain significance ★★ ⚠ same condition
ATN1 p.Pro970Ser Uncertain significance ★★ ⚠ same condition
ATN1 p.Ser379Ile Uncertain significance ★★ ⚠ same condition
ATN1 p.Val911Met Uncertain significance ★★ ⚠ same condition

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/atn1-p-pro720ser (accessed [today's date]).

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