Is ERI3 p.Ala74Ser (c.220G>T) pathogenic?

ERI3 p.Ala74Ser (c.220G>T) is classified Uncertain significance in ERI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). AlphaMissense: likely benign (0.0894); Very rare (popmax 0.0031%, eas).

How common is ERI3 p.Ala74Ser (c.220G>T) in the general population?

ERI3 p.Ala74Ser (c.220G>T) is very rare (popmax 0.0031%, eas) (gnomAD).

What do computational predictors say about ERI3 p.Ala74Ser (c.220G>T)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

ERI3 p.Ala74Ser

c.220G>T · rs1301579877 · VCV2559662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0031%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -5.70	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 3.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 118 kb · p 1.7e-16 · regional, not allelic
Overall
CADD	26.0	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 0.0031% East Asian · 1/32,268 alleles

Filtering AF 3.5e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.3e-05%

Overall 0.000485% 6/1,238,092 alleles · very rare exomes 6/1,112,506 · genomes 0/125,586 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0031%	32,268
Remaining individualsnot grpmax-eligible	0.0022%	45,480
South Asian	0.00216%	46,360
Finnishnot grpmax-eligible	0.00211%	47,474
European (non-Finnish)	0.000211%	474,334

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: ERI3
Protein: p.Ala74Ser
Coding: c.220G>T
MANE Select: NM_024066
dbSNP: rs1301579877
Type: single nucleotide variant
Location: chr1:44339314 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 75.08 · 7 PDB

Full ERI3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERI3 p.Ala229Val Uncertain significance ★ ⚠ same type
ERI3 p.Arg176Gln Uncertain significance ★ ⚠ same type
ERI3 p.Arg326Gln Uncertain significance ★ ⚠ same type
ERI3 p.Asp156Asn Uncertain significance ★ ⚠ same type
ERI3 p.Asp73Gly Uncertain significance ★ ⚠ same type
ERI3 p.Glu17Lys Uncertain significance ★ ⚠ same type
ERI3 p.Glu226Gly Uncertain significance ★ ⚠ same type
ERI3 p.Gly127Asp 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/eri3-p-ala74ser (accessed [today's date]).

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