Is EXOSC2 p.Ala143= (c.429T>C) pathogenic?

EXOSC2 p.Ala143= (c.429T>C) is classified Benign in EXOSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Common (popmax 8.12%, eas) — too common for a highly-penetrant pathogenic allele.

EXOSC2 p.Ala143=

Q: How common is EXOSC2 p.Ala143= (c.429T>C) in the general population?

EXOSC2 p.Ala143= (c.429T>C) is common (popmax 8.12%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.429T>C · rs117012336 · VCV779928

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 8.12%, eas) — too common for a highly-penetrant pathogenic allele

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 -1.6	GERP -4.7
Overall
CADD	6.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.12% East Asian · 3,641/44,856 alleles

Filtering AF 7.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.81%

Overall 0.289% 4,665/1,614,020 alleles · common exomes 4,071/1,461,780 · genomes 594/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	8.12%	12
Remaining individualsnot grpmax-eligible	0.838%	119
Finnishnot grpmax-eligible	0.239%	419
South Asian	0.199%	503
Middle Eastern	0.0496%	2,015
African / African-American	0.04%	2,500
Admixed American	0.0333%	3,000
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
European (non-Finnish)	0.00907%	11,028

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: EXOSC2
Protein: p.Ala143=
Coding: c.429T>C
MANE Select: NM_014285
dbSNP: rs117012336
Type: single nucleotide variant
Location: chr9:130700869 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 143: the s1 motif domain

Full EXOSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC2 p.Ala143Ser Uncertain significance ★ same residue
EXOSC2 p.Ala143Thr Uncertain significance ★ ⚠ same residue
EXOSC2 p.Arg181Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg236Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg238Gln Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg238Trp Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg285Cys Uncertain significance ★★ ⚠ same type
EXOSC2 p.Arg62Thr 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/exosc2-p-ala143 (accessed [today's date]).

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