Is AEN p.Ala230Thr (c.688G>A) pathogenic?

AEN p.Ala230Thr (c.688G>A) is classified Likely benign in AEN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.0705); Ultra-rare (popmax 0.0132%, sas).

How common is AEN p.Ala230Thr (c.688G>A) in the general population?

AEN p.Ala230Thr (c.688G>A) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about AEN p.Ala230Thr (c.688G>A)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

AEN p.Ala230Thr

c.688G>A · rs763291238 · VCV3091557

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -5.72	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 1.6	GERP -4.9, phastCons 0.17
Regional constraint	o/e 1.06	unconstrained · MANE · 4,081 bp · p 0.21 · regional, not allelic
Overall
CADD	8.633	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,074 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000821% 12/1,461,844 alleles · ultra-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: AEN
Protein: p.Ala230Thr
Coding: c.688G>A
MANE Select: NM_022767
dbSNP: rs763291238
Type: single nucleotide variant
Location: chr15:88629373 (GRCh38)
Gene constraint: LOEUF 1.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19
Residue 230: the exonuclease domain

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

Similar variants

AEN p.Ala10Ser Uncertain significance ★ ⚠ same type
AEN p.Ala112Ser Uncertain significance ★ ⚠ same type
AEN p.Ala194Thr Uncertain significance ★ ⚠ same type
AEN p.Ala201Val Uncertain significance ★ ⚠ same type
AEN p.Ala45Ser Uncertain significance ★ ⚠ same type
AEN p.Arg125Trp Uncertain significance ★ ⚠ same type
AEN p.Arg131Cys Uncertain significance ★ ⚠ same type
AEN p.Arg131His 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/aen-p-ala230thr (accessed [today's date]).

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