Is ERGIC2 p.Thr9Ala (c.25A>G) pathogenic?

ERGIC2 p.Thr9Ala (c.25A>G) is classified Uncertain significance in ERGIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0132%, sas).

How common is ERGIC2 p.Thr9Ala (c.25A>G) in the general population?

ERGIC2 p.Thr9Ala (c.25A>G) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about ERGIC2 p.Thr9Ala (c.25A>G)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

ERGIC2 p.Thr9Ala

c.25A>G · VCV4665110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · 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	0.0853	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -4.66	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 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 30 kb · p 0.0048 · regional, not allelic
Overall
CADD	18.6	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 0.0132% South Asian · 12/90,968 alleles

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

Overall 0.00089% 13/1,460,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,581
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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: ERGIC2
Protein: p.Thr9Ala
Coding: c.25A>G
MANE Select: NM_016570
Type: single nucleotide variant
Location: chr12:29371609 (GRCh38)
Gene constraint: LOEUF 1.266 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.21

Full ERGIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERGIC2 c.572+5G>A Pathogenic ★ same type
ERGIC2 p.Ala240Ser Uncertain significance ★ ⚠ same type
ERGIC2 p.Ala283Glu Uncertain significance ★ ⚠ same type
ERGIC2 p.Arg197Cys Uncertain significance ★ ⚠ same type
ERGIC2 p.Arg277Pro Uncertain significance ★ ⚠ same type
ERGIC2 p.Arg346His Uncertain significance ★ ⚠ same type
ERGIC2 p.Asn179Ser Uncertain significance ★ ⚠ same type
ERGIC2 p.Asn356Ser 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/ergic2-p-thr9ala (accessed [today's date]).

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