Is ACER2 p.Arg119Pro (c.356G>C) pathogenic?

ACER2 p.Arg119Pro (c.356G>C) is classified Uncertain significance in ACER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.3987); Very rare (popmax 0.000169%, nfe).

How common is ACER2 p.Arg119Pro (c.356G>C) in the general population?

ACER2 p.Arg119Pro (c.356G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ACER2 p.Arg119Pro (c.356G>C)?

AlphaMissense predicts ambiguous (score 0.3987) — an in-silico prediction, not a clinical call.

ACER2 p.Arg119Pro

c.356G>C · VCV4215375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3987	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -14.25	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 42 kb · p 0.55 · regional, not allelic
Overall
CADD	29.0	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 0.000169% European (non-Finnish) · 2/1,180,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,838 alleles · very rare

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: ACER2
Protein: p.Arg119Pro
Coding: c.356G>C
MANE Select: NM_001010887
Type: single nucleotide variant
Location: chr9:19424832 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.23

Full ACER2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACER2 p.Arg112Lys Uncertain significance ★ ⚠ same type
ACER2 p.Arg112Ser Uncertain significance ★ ⚠ same type
ACER2 p.Arg122Trp Uncertain significance ★ ⚠ same type
ACER2 p.Arg124Gly Uncertain significance ★ ⚠ same type
ACER2 p.Arg196Gln Uncertain significance ★ ⚠ same type
ACER2 p.Arg196Gly Uncertain significance ★ ⚠ same type
ACER2 p.Asn147Ser Uncertain significance ★ ⚠ same type
ACER2 p.Asn23Lys 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/acer2-p-arg119pro (accessed [today's date]).

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