Is ERGIC1 p.Arg246Trp (c.736C>T) pathogenic?

ERGIC1 p.Arg246Trp (c.736C>T) is classified Uncertain significance in ERGIC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.2584); Very rare (popmax 0.00415%, nfe).

How common is ERGIC1 p.Arg246Trp (c.736C>T) in the general population?

ERGIC1 p.Arg246Trp (c.736C>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about ERGIC1 p.Arg246Trp (c.736C>T)?

AlphaMissense predicts likely benign (score 0.2584) — an in-silico prediction, not a clinical call.

ERGIC1 p.Arg246Trp

c.736C>T · rs774919836 · VCV2242824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2584	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -13.05	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 0.81	GERP -0.24, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 8,765 bp · p 0.73 · regional, not allelic
Overall
CADD	26.3	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 0.00415% European (non-Finnish) · 49/1,180,050 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.0031% 50/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,083
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg246Trp
Coding: c.736C>T
MANE Select: NM_001031711
dbSNP: rs774919836
Type: single nucleotide variant
Location: chr5:172935281 (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.Asn180Ser Uncertain significance ★ ⚠ same type
ERGIC1 p.Asp102Ala 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-arg246trp (accessed [today's date]).

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