Is ERC1 p.Glu220Ala (c.659A>C) pathogenic?

ERC1 p.Glu220Ala (c.659A>C) is classified Uncertain significance in ERC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: ambiguous (0.4936); Ultra-rare (popmax 0.0274%, nfe).

How common is ERC1 p.Glu220Ala (c.659A>C) in the general population?

ERC1 p.Glu220Ala (c.659A>C) is ultra-rare (popmax 0.0274%, nfe) (gnomAD).

What do computational predictors say about ERC1 p.Glu220Ala (c.659A>C)?

AlphaMissense predicts ambiguous (score 0.4936) — an in-silico prediction, not a clinical call.

ERC1 p.Glu220Ala

c.659A>C · VCV3509771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0274%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4936	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -8.58	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 462 kb · p 5.7e-05 · regional, not allelic
Overall
CADD	26.7	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 0.0274% European (non-Finnish) · 323/1,176,746 alleles

Filtering AF 0.0249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.0212% 340/1,607,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0274%	3,643
Remaining individualsnot grpmax-eligible	0.0193%	5,174
African / African-American	0.00403%	24,818
Admixed American	0.00341%	29,352

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: ERC1
Protein: p.Glu220Ala
Coding: c.659A>C
MANE Select: NM_178040
Type: single nucleotide variant
Location: chr12:1028562 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 75.64

Full ERC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC1 p.Ser393= Benign ★★ same type
ERC1 c.3214-1G>A Uncertain significance ★ same type
ERC1 p.Ala1058Val Uncertain significance ★ ⚠ same type
ERC1 p.Ala199Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala260Glu Uncertain significance ★ ⚠ same type
ERC1 p.Ala5Ser Uncertain significance ★ ⚠ same type
ERC1 p.Ala621Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala682Ser 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/erc1-p-glu220ala (accessed [today's date]).

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