Is ERGIC2 p.Pro194Ala (c.580C>G) pathogenic?

ERGIC2 p.Pro194Ala (c.580C>G) is classified Uncertain significance in ERGIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely benign (0.261); Very rare (popmax 0.00669%, afr).

How common is ERGIC2 p.Pro194Ala (c.580C>G) in the general population?

ERGIC2 p.Pro194Ala (c.580C>G) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about ERGIC2 p.Pro194Ala (c.580C>G)?

AlphaMissense predicts likely benign (score 0.261) — an in-silico prediction, not a clinical call.

ERGIC2 p.Pro194Ala

c.580C>G · VCV3510073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.261	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -6.37	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 30 kb · p 0.0048 · regional, not allelic
Overall
CADD	24.6	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 0.00669% African / African-American · 5/74,710 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000562% 9/1,600,256 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,942
Admixed American	0.00501%	19,953
Remaining individualsnot grpmax-eligible	0.00162%	61,886

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.Pro194Ala
Coding: c.580C>G
MANE Select: NM_016570
Type: single nucleotide variant
Location: chr12:29350061 (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-pro194ala (accessed [today's date]).

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