Is AREG p.Pro110His (c.329C>A) pathogenic?

AREG p.Pro110His (c.329C>A) is classified Uncertain significance in AREG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: ambiguous (0.3982); Ultra-rare (popmax 0.0136%, amr).

How common is AREG p.Pro110His (c.329C>A) in the general population?

AREG p.Pro110His (c.329C>A) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about AREG p.Pro110His (c.329C>A)?

AlphaMissense predicts ambiguous (score 0.3982) — an in-silico prediction, not a clinical call.

AREG p.Pro110His

c.329C>A · VCV3888194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3982	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -7.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
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	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0136% Admixed American · 8/59,016 alleles

Filtering AF 0.00671% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00489%

Overall 0.00317% 51/1,608,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,377
European (non-Finnish)	0.00339%	29,477
East Asian	0.00224%	44,668
Remaining individualsnot grpmax-eligible	0.0016%	62,328
South Asian	0.00111%	90,440

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.Pro110His
Coding: c.329C>A
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.Pro110Leu 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-pro110his (accessed [today's date]).

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