Is AGR2 p.Val90Met (c.268G>A) pathogenic?

AGR2 p.Val90Met (c.268G>A) is classified Uncertain significance in AGR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.228); Very rare (popmax 0.00267%, afr).

How common is AGR2 p.Val90Met (c.268G>A) in the general population?

AGR2 p.Val90Met (c.268G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about AGR2 p.Val90Met (c.268G>A)?

AlphaMissense predicts likely benign (score 0.228) — an in-silico prediction, not a clinical call.

AGR2 p.Val90Met

c.268G>A · rs372209181 · VCV2371780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.228	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -9.18	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 4	GERP 0.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,885 bp · p 0.18 · regional, not allelic
Overall
CADD	22.6	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 0.00267% African / African-American · 2/74,832 alleles

Filtering AF 0.00069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.00559% 90/1,610,368 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.206%	484
Remaining individualsnot grpmax-eligible	0.0208%	4,797
African / African-Americangrpmax	0.00267%	37,416
European (non-Finnish)	0.00119%	84,089

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: AGR2
Protein: p.Val90Met
Coding: c.268G>A
MANE Select: NM_006408
dbSNP: rs372209181
Type: single nucleotide variant
Location: chr7:16799806 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.52 · 5 PDB
Residue 90: an α-helix

Full AGR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGR2 c.256+2T>C Likely pathogenic ★ same type
AGR2 c.257-1G>C Likely pathogenic ★ same type
AGR2 c.330+1G>T Pathogenic ★ same type
AGR2 p.His117Tyr Likely pathogenic ★ ⚠ same type
AGR2 p.Pro71Thr Likely pathogenic ★ same type
AGR2 p.Trp54Ter Likely pathogenic ★ same type
AGR2 p.Arg148Ser Uncertain significance ★ ⚠ same type
AGR2 p.Arg21Ile 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/agr2-p-val90met (accessed [today's date]).

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