Is ERI3 p.Ser22Phe (c.65C>T) pathogenic?

ERI3 p.Ser22Phe (c.65C>T) is classified Uncertain significance in ERI3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-16). AlphaMissense: likely benign (0.2839); Ultra-rare (popmax 0.0251%, eas).

How common is ERI3 p.Ser22Phe (c.65C>T) in the general population?

ERI3 p.Ser22Phe (c.65C>T) is ultra-rare (popmax 0.0251%, eas) (gnomAD).

What do computational predictors say about ERI3 p.Ser22Phe (c.65C>T)?

AlphaMissense predicts likely benign (score 0.2839) — an in-silico prediction, not a clinical call.

ERI3 p.Ser22Phe

c.65C>T · VCV3276346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2839	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -8.23	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 7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 16 kb · p 0.3 · regional, not allelic
Overall
CADD	26.3	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 0.0251% East Asian · 9/35,872 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00969%

Overall 0.00208% 28/1,346,866 alleles · ultra-rare exomes 25/1,194,664 · genomes 3/152,202 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0251%	3,986
European (non-Finnish)	0.00173%	57,901
African / African-American	0.0015%	66,624

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.Ser22Phe
Coding: c.65C>T
MANE Select: NM_024066
Type: single nucleotide variant
Location: chr1:44354962 (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.Ala74Ser 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

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-ser22phe (accessed [today's date]).

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