Is ENDOG p.Ala143Asp (c.428C>A) pathogenic?

ENDOG p.Ala143Asp (c.428C>A) is classified Uncertain significance in ENDOG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9969); Very rare (popmax 8.8e-05%, nfe).

How common is ENDOG p.Ala143Asp (c.428C>A) in the general population?

ENDOG p.Ala143Asp (c.428C>A) is very rare (popmax 8.8e-05%, nfe) (gnomAD).

What do computational predictors say about ENDOG p.Ala143Asp (c.428C>A)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

ENDOG p.Ala143Asp

c.428C>A · VCV4017968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.8e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic · top 1% in ENDOG
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,922 bp · p 0.17 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.8e-05% European (non-Finnish) · 1/1,136,920 alleles

Overall 7.32e-05% 1/1,366,744 alleles · very 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: ENDOG
Protein: p.Ala143Asp
Coding: c.428C>A
MANE Select: NM_004435
Type: single nucleotide variant
Location: chr9:128819112 (GRCh38)
Gene constraint: LOEUF 1.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.67 · 2 PDB

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

Similar variants

ENDOG p.Arg184Cys Uncertain significance ★★ ⚠ same type
ENDOG p.Ile218= Benign ★★ same type
ENDOG p.Thr246Ile Benign ★★ ⚠ same type
ENDOG p.Ala130Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala14Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala252Val Uncertain significance ★ ⚠ same type
ENDOG p.Ala284Val Uncertain significance ★ ⚠ same type
ENDOG p.Arg103His 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/endog-p-ala143asp (accessed [today's date]).

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