Is ERGIC2 p.Arg277Pro (c.830G>C) pathogenic?

ERGIC2 p.Arg277Pro (c.830G>C) is classified Uncertain significance in ERGIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 8.62e-05%, nfe).

How common is ERGIC2 p.Arg277Pro (c.830G>C) in the general population?

ERGIC2 p.Arg277Pro (c.830G>C) is very rare (popmax 8.62e-05%, nfe) (gnomAD).

What do computational predictors say about ERGIC2 p.Arg277Pro (c.830G>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

ERGIC2 p.Arg277Pro

c.830G>C · VCV4250685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.62e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 1% in ERGIC2
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -17.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 30 kb · p 0.0048 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.62e-05% European (non-Finnish) · 1/1,160,146 alleles

Overall 7.02e-05% 1/1,424,480 alleles · very rare

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.Arg277Pro
Coding: c.830G>C
MANE Select: NM_016570
Type: single nucleotide variant
Location: chr12:29343278 (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.Arg346His Uncertain significance ★ ⚠ same type
ERGIC2 p.Asn179Ser Uncertain significance ★ ⚠ same type
ERGIC2 p.Asn356Ser Uncertain significance ★ ⚠ same type
ERGIC2 p.Asn375Ser 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-arg277pro (accessed [today's date]).

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