Is AREG p.Pro110Leu (c.329C>T) pathogenic?

AREG p.Pro110Leu (c.329C>T) is classified Uncertain significance in AREG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-29). AlphaMissense: likely benign (0.3019); Ultra-rare (popmax 0.0165%, mid).

How common is AREG p.Pro110Leu (c.329C>T) in the general population?

AREG p.Pro110Leu (c.329C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AREG p.Pro110Leu (c.329C>T)?

AlphaMissense predicts likely benign (score 0.3019) — an in-silico prediction, not a clinical call.

AREG p.Pro110Leu

c.329C>T · VCV4641987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3019 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3019	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -6.26	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 2.8	GERP 1.8, phastCons 0.95
Regional constraint	o/e 0.93	unconstrained · MANE · 7,288 bp · p 0.21 · regional, not allelic
Overall
CADD	25.1	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0082%

Overall 0.00802% 129/1,608,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
European (non-Finnish)	0.0103%	9,745
Remaining individualsnot grpmax-eligible	0.00963%	10,384
East Asian	0.00224%	44,680

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.Pro110Leu
Coding: c.329C>T
MANE Select: NM_001657
Type: single nucleotide variant
Location: chr4:74449065 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.00 · 1 PDB
Residue 110: the 'disordered' region

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

Similar variants

AREG p.Pro110His Uncertain significance ★ ⚠ same residue
AREG p.Ala3Pro Uncertain significance ★ ⚠ same type
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

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-pro110leu (accessed [today's date]).

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