Is ACOT1 p.Pro89= (c.267C>T) pathogenic?

ACOT1 p.Pro89= (c.267C>T) is classified Likely benign in ACOT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Rare (popmax 0.232%, sas).

How common is ACOT1 p.Pro89= (c.267C>T) in the general population?

ACOT1 p.Pro89= (c.267C>T) is rare (popmax 0.232%, sas) (gnomAD).

ACOT1 p.Pro89=

c.267C>T · rs766196827 · VCV778485

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.232%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.6
Overall
CADD	1.828	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.232% South Asian · 166/71,632 alleles

Filtering AF 0.203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.192%

Overall 0.143% 1,737/1,215,744 alleles · rare exomes 1,556/1,100,042 · genomes 181/115,702 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.363%	275
Amishnot grpmax-eligible	0.331%	302
South Asiangrpmax	0.232%	432
Middle Eastern	0.167%	600
Remaining individualsnot grpmax-eligible	0.155%	646
Admixed American	0.15%	666
European (non-Finnish)	0.137%	728
African / African-American	0.0431%	2,320
Ashkenazi Jewishnot grpmax-eligible	0.0133%	7,505

Finnish 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: ACOT1
Protein: p.Pro89=
Coding: c.267C>T
MANE Select: NM_001037161
dbSNP: rs766196827
Type: single nucleotide variant
Location: chr14:73537688 (GRCh38)
Gene constraint: LOEUF 1.531 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 96.65

Full ACOT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT1 p.Pro89Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
HEATR4 p.Ser89Asn Uncertain significance ★ ⚠ same residue
HEATR4 p.Gly590Ser Uncertain significance ★★ ⚠ same type
ACOT1 p.Ala50= Benign ★★ same type
ACOT1 p.Gly276Ala Benign ★★ same type
ACOT1 p.His413Arg Likely benign ★★ same type
RIOX1 p.Arg529= Benign/Likely benign ★★ same type
ACOT1 p.Ala179Pro 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/acot1-p-pro89 (accessed [today's date]).

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