Is ERI2 p.Leu450Ser (c.1349T>C) pathogenic?

ERI2 p.Leu450Ser (c.1349T>C) is classified Likely benign in ERI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0498); Low-frequency (popmax 1.66%, eas).

How common is ERI2 p.Leu450Ser (c.1349T>C) in the general population?

ERI2 p.Leu450Ser (c.1349T>C) is low-frequency (popmax 1.66%, eas) (gnomAD).

What do computational predictors say about ERI2 p.Leu450Ser (c.1349T>C)?

AlphaMissense predicts likely benign (score 0.0498) — an in-silico prediction, not a clinical call.

ERI2 p.Leu450Ser

c.1349T>C · VCV4250724

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0498 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0498	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 0.89
Regional constraint	o/e 0.87	unconstrained · MANE · 8,703 bp · p 0.00034 · regional, not allelic
Overall
CADD	2.542	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 1.66% East Asian · 678/40,916 alleles

Filtering AF 1.55% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.51%

Overall 0.236% 3,665/1,551,020 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.66%	60
European (non-Finnish)	0.23%	436
Remaining individualsnot grpmax-eligible	0.221%	452
Finnishnot grpmax-eligible	0.159%	630
South Asian	0.099%	1,010
African / African-American	0.0342%	2,925
Ashkenazi Jewishnot grpmax-eligible	0.0314%	3,180
Admixed American	0.0177%	5,655

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: ERI2
Protein: p.Leu450Ser
Coding: c.1349T>C
MANE Select: NM_001142725
Type: single nucleotide variant
Location: chr16:20798451 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.66 · 2 PDB

Full ERI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSM3 p.Asn444His Uncertain significance ★ ⚠ same type
ACSM3 p.Gly260Ala Uncertain significance ★ ⚠ same type
ACSM3 p.Pro268Arg Uncertain significance ★ ⚠ same type
ACSM3 p.Trp273Arg Uncertain significance ★ ⚠ same type
ACSM3 p.Tyr457Cys Uncertain significance ★ ⚠ same type
ERI2 p.Ala102Ser Uncertain significance ★ ⚠ same type
ERI2 p.Ala19Val Uncertain significance ★ ⚠ same type
ERI2 p.Ala200Val 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/eri2-p-leu450ser (accessed [today's date]).

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