Is ESD p.Thr57Ala (c.169A>G) pathogenic?

ESD p.Thr57Ala (c.169A>G) is classified Uncertain significance in ESD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: ambiguous (0.4837); Very rare (popmax 0.00535%, afr).

How common is ESD p.Thr57Ala (c.169A>G) in the general population?

ESD p.Thr57Ala (c.169A>G) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about ESD p.Thr57Ala (c.169A>G)?

AlphaMissense predicts ambiguous (score 0.4837) — an in-silico prediction, not a clinical call.

ESD p.Thr57Ala

c.169A>G · rs943899803 · VCV3090433

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Computational evidence

Protein change
AlphaMissense	0.4837	ambiguous
REVEL	0.536	indeterminate
SaProt	LLR -12.77	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 20 kb · p 0.71 · regional, not allelic
Overall
CADD	26.9	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 0.00535% African / African-American · 4/74,704 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000373% 6/1,609,386 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,676
Remaining individualsnot grpmax-eligible	0.00321%	31,159

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: ESD
Protein: p.Thr57Ala
Coding: c.169A>G
MANE Select: NM_001984
dbSNP: rs943899803
Type: single nucleotide variant
Location: chr13:46784339 (GRCh38)
Gene constraint: LOEUF 1.515 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.28 · 1 PDB

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

Similar variants

ESD p.Asp271= Benign ★★ same type
ESD p.Thr116= Benign/Likely benign ★★ same type
ESD p.Ala173Pro Uncertain significance ★ ⚠ same type
ESD p.Ala242Val Uncertain significance ★ ⚠ same type
ESD p.Ala33Gly Uncertain significance ★ ⚠ same type
ESD p.Arg119Lys Uncertain significance ★ ⚠ same type
ESD p.Arg253Gln Uncertain significance ★ ⚠ same type
ESD p.Asn135Ser 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/esd-p-thr57ala (accessed [today's date]).

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