Is ERN2 p.Thr57= (c.171A>T) pathogenic?

ERN2 p.Thr57= (c.171A>T) is classified Likely benign in ERN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). Ultra-rare (popmax 0.05%, amr).

How common is ERN2 p.Thr57= (c.171A>T) in the general population?

ERN2 p.Thr57= (c.171A>T) is ultra-rare (popmax 0.05%, amr) (gnomAD).

ERN2 p.Thr57=

c.171A>T · rs55780778 · VCV3024691

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

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 -3.4
Overall
CADD	0.316	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.05% Admixed American · 30/60,026 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.033% 532/1,614,076 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.284%	352
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Admixed Americangrpmax	0.05%	2,001
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0319%	3,138
African / African-American	0.004%	25,020
Finnishnot grpmax-eligible	0.00312%	32,020

Ashkenazi Jewish 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: ERN2
Protein: p.Thr57=
Coding: c.171A>T
MANE Select: NM_033266
dbSNP: rs55780778
Type: single nucleotide variant
Location: chr16:23710941 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.91 · 2 PDB

Full ERN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERN2 p.Arg868Ter Uncertain significance ★★ same type
ERN2 p.Val69Ile Benign ★★ ⚠ same type
ERN2 p.Ala22Val Uncertain significance ★ ⚠ same type
ERN2 p.Ala318Asp Uncertain significance ★ ⚠ same type
ERN2 p.Ala395Val Uncertain significance ★ ⚠ same type
ERN2 p.Ala4Thr Uncertain significance ★ ⚠ same type
ERN2 p.Ala760Thr Uncertain significance ★ ⚠ same type
ERN2 p.Ala80Thr 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/ern2-p-thr57 (accessed [today's date]).

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