Is ERGIC3 p.Pro80Ser (c.238C>T) pathogenic?

ERGIC3 p.Pro80Ser (c.238C>T) is classified Uncertain significance in ERGIC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.9263); Very rare (popmax 0.00534%, afr).

How common is ERGIC3 p.Pro80Ser (c.238C>T) in the general population?

ERGIC3 p.Pro80Ser (c.238C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ERGIC3 p.Pro80Ser (c.238C>T)?

AlphaMissense predicts likely pathogenic (score 0.9263) — an in-silico prediction, not a clinical call.

ERGIC3 p.Pro80Ser

c.238C>T · VCV3846011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9263	likely pathogenic
REVEL	0.287	benign-leaning
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 15 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,892 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,804 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,723
European (non-Finnish)	8.47e-05%	1,179,956

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: ERGIC3
Protein: p.Pro80Ser
Coding: c.238C>T
MANE Select: NM_015966
Type: single nucleotide variant
Location: chr20:35542591 (GRCh38)
Gene constraint: LOEUF 0.781 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.05

Full ERGIC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERGIC3 c.718-4A>G Benign ★★ same type
ERGIC3 p.Leu295= Benign ★★ same type
ERGIC3 c.686-664G>A Uncertain significance ★ same type
ERGIC3 c.717+1G>A Uncertain significance ★ same type
ERGIC3 p.Arg121Gln Uncertain significance ★ ⚠ same type
ERGIC3 p.Arg163Gln Uncertain significance ★ ⚠ same type
ERGIC3 p.Arg163Trp Uncertain significance ★ ⚠ same type
ERGIC3 p.Arg167Cys 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/ergic3-p-pro80ser (accessed [today's date]).

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