Is ERGIC1 p.Pro61Thr (c.181C>A) pathogenic?

ERGIC1 p.Pro61Thr (c.181C>A) is classified Uncertain significance in ERGIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely pathogenic (0.7024); Very rare (popmax 0.00133%, afr).

How common is ERGIC1 p.Pro61Thr (c.181C>A) in the general population?

ERGIC1 p.Pro61Thr (c.181C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ERGIC1 p.Pro61Thr (c.181C>A)?

AlphaMissense predicts likely pathogenic (score 0.7024) — an in-silico prediction, not a clinical call.

ERGIC1 p.Pro61Thr

c.181C>A · VCV3510067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7024	likely pathogenic
REVEL	0.423	indeterminate
SaProt	LLR -10.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 92 kb · p 2.9e-05 · regional, not allelic
Overall
CADD	26.2	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 0.00133% African / African-American · 1/74,928 alleles

Overall 0.000657% 1/152,200 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: ERGIC1
Protein: p.Pro61Thr
Coding: c.181C>A
MANE Select: NM_001031711
Type: single nucleotide variant
Location: chr5:172909692 (GRCh38)
Gene constraint: LOEUF 0.683 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 88.96

Full ERGIC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERGIC1 c.250+1G>A Likely pathogenic ★ same type
ERGIC1 c.155+1G>A Uncertain significance ★ same type
ERGIC1 p.Ala228Glu Uncertain significance ★ ⚠ same type
ERGIC1 p.Ala267Thr Uncertain significance ★ ⚠ same type
ERGIC1 p.Arg116Cys Uncertain significance ★ ⚠ same type
ERGIC1 p.Arg232His Uncertain significance ★ ⚠ same type
ERGIC1 p.Arg246Trp Uncertain significance ★ ⚠ same type
ERGIC1 p.Asn180Ser 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/ergic1-p-pro61thr (accessed [today's date]).

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