Is AREG p.Ala3Pro (c.7G>C) pathogenic?

AREG p.Ala3Pro (c.7G>C) is classified Uncertain significance in AREG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely benign (0.1119); Ultra-rare (popmax 0.0117%, amr).

How common is AREG p.Ala3Pro (c.7G>C) in the general population?

AREG p.Ala3Pro (c.7G>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about AREG p.Ala3Pro (c.7G>C)?

AlphaMissense predicts likely benign (score 0.1119) — an in-silico prediction, not a clinical call.

AREG p.Ala3Pro

c.7G>C · rs750666473 · VCV2514678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1119	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.72	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 0.24	GERP -3, phastCons 0.002
Regional constraint	o/e 0.93	unconstrained · MANE · 7,288 bp · p 0.21 · regional, not allelic
Overall
CADD	19.42	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 0.0117% Admixed American · 7/59,862 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00348% 56/1,610,448 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,552
European (non-Finnish)	0.00407%	24,571
Remaining individualsnot grpmax-eligible	0.00161%	62,204

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: AREG
Protein: p.Ala3Pro
Coding: c.7G>C
MANE Select: NM_001657
dbSNP: rs750666473
Type: single nucleotide variant
Location: chr4:74445352 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.00 · 1 PDB

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

Similar variants

AREG p.Arg37His Uncertain significance ★ ⚠ same type
AREG p.Asn113Lys Uncertain significance ★ ⚠ same type
AREG p.Asp80Asn Uncertain significance ★ ⚠ same type
AREG p.Asp88Glu Uncertain significance ★ ⚠ same type
AREG p.Asp99Asn Uncertain significance ★ ⚠ same type
AREG p.Gln106Arg Uncertain significance ★ ⚠ same type
AREG p.Glu118Gln Uncertain significance ★ ⚠ same type
AREG p.Glu118Lys 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/areg-p-ala3pro (accessed [today's date]).

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