Is ERGIC1 p.Pro108Leu (c.323C>T) pathogenic?

ERGIC1 p.Pro108Leu (c.323C>T) is classified Uncertain significance in ERGIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: likely benign (0.1976); Ultra-rare (popmax 0.0231%, sas).

How common is ERGIC1 p.Pro108Leu (c.323C>T) in the general population?

ERGIC1 p.Pro108Leu (c.323C>T) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

What do computational predictors say about ERGIC1 p.Pro108Leu (c.323C>T)?

AlphaMissense predicts likely benign (score 0.1976) — an in-silico prediction, not a clinical call.

ERGIC1 p.Pro108Leu

c.323C>T · VCV3276327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1976 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1976	likely benign
REVEL	0.523	indeterminate
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 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	30.0	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 0.0231% South Asian · 21/91,084 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00242% 39/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,337
East Asian	0.0111%	8,980
African / African-American	0.00267%	37,459
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000763%	131,117

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.Pro108Leu
Coding: c.323C>T
MANE Select: NM_001031711
Type: single nucleotide variant
Location: chr5:172914786 (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-pro108leu (accessed [today's date]).

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