Is ERC2 p.Arg94Cys (c.280C>T) pathogenic?

ERC2 p.Arg94Cys (c.280C>T) is classified Uncertain significance in ERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.8893); Very rare (popmax 0.00432%, nfe).

How common is ERC2 p.Arg94Cys (c.280C>T) in the general population?

ERC2 p.Arg94Cys (c.280C>T) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about ERC2 p.Arg94Cys (c.280C>T)?

AlphaMissense predicts likely pathogenic (score 0.8893) — an in-silico prediction, not a clinical call.

ERC2 p.Arg94Cys

c.280C>T · VCV4250464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8893	likely pathogenic
REVEL	0.268	benign-leaning
SaProt	LLR -11.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 139 kb · p 0.13 · regional, not allelic
Overall
CADD	28.9	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 0.00432% European (non-Finnish) · 51/1,179,888 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00335% 54/1,613,806 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,135
African / African-American	0.00401%	24,961

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: ERC2
Protein: p.Arg94Cys
Coding: c.280C>T
MANE Select: NM_015576
Type: single nucleotide variant
Location: chr3:56434728 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.26

Full ERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC2 p.Ala105Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala107Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala202Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala251Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala333Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala371Pro Uncertain significance ★ ⚠ same type
ERC2 p.Ala724Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala835Thr 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/erc2-p-arg94cys (accessed [today's date]).

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