Is ERC2 p.Glu718Lys (c.2152G>A) pathogenic?

ERC2 p.Glu718Lys (c.2152G>A) is classified Uncertain significance in ERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.2884); Ultra-rare (popmax 0.01%, amr).

How common is ERC2 p.Glu718Lys (c.2152G>A) in the general population?

ERC2 p.Glu718Lys (c.2152G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ERC2 p.Glu718Lys (c.2152G>A)?

AlphaMissense predicts likely benign (score 0.2884) — an in-silico prediction, not a clinical call.

ERC2 p.Glu718Lys

c.2152G>A · rs751851932 · VCV2301609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2884	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 323 kb · p 0.17 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,998 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00192% 31/1,613,814 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
East Asian	0.00223%	44,892
European (non-Finnish)	0.00195%	51,298
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Glu718Lys
Coding: c.2152G>A
MANE Select: NM_015576
dbSNP: rs751851932
Type: single nucleotide variant
Location: chr3:55992160 (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-glu718lys (accessed [today's date]).

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