Is ERC2 p.Thr373Ala (c.1117A>G) pathogenic?

ERC2 p.Thr373Ala (c.1117A>G) is classified Uncertain significance in ERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.2133); Very rare (popmax 0.00267%, afr).

How common is ERC2 p.Thr373Ala (c.1117A>G) in the general population?

ERC2 p.Thr373Ala (c.1117A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ERC2 p.Thr373Ala (c.1117A>G)?

AlphaMissense predicts likely benign (score 0.2133) — an in-silico prediction, not a clinical call.

ERC2 p.Thr373Ala

c.1117A>G · VCV4019182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2133	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 156 kb · p 0.38 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,462
European (non-Finnish)	0.00229%	43,698
South Asian	0.0011%	91,082

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: ERC2
Protein: p.Thr373Ala
Coding: c.1117A>G
MANE Select: NM_015576
Type: single nucleotide variant
Location: chr3:56173478 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.26

Full ERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC2 p.Ala105Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala107Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala202Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala251Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala333Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala371Pro Uncertain significance ★ ⚠ same type
ERC2 p.Ala724Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala835Thr 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/erc2-p-thr373ala (accessed [today's date]).

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