Is ERI2 p.Ser44Leu (c.131C>T) pathogenic?

ERI2 p.Ser44Leu (c.131C>T) is classified Uncertain significance in ERI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.7577); Ultra-rare (popmax 0.0165%, mid).

How common is ERI2 p.Ser44Leu (c.131C>T) in the general population?

ERI2 p.Ser44Leu (c.131C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ERI2 p.Ser44Leu (c.131C>T)?

AlphaMissense predicts likely pathogenic (score 0.7577) — an in-silico prediction, not a clinical call.

ERI2 p.Ser44Leu

c.131C>T · VCV4250714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7577	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -14.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.29	donor loss, 44 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 0.87, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,703 bp · p 0.00034 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00235% 38/1,613,910 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00769%	13,008
Remaining individualsnot grpmax-eligible	0.0048%	20,833
European (non-Finnish)	0.000763%	131,097

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser44Leu
Coding: c.131C>T
MANE Select: NM_001142725
Type: single nucleotide variant
Location: chr16:20803477 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.66 · 2 PDB
Residue 44: the exonuclease domain

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-ser44leu (accessed [today's date]).

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