Is ACER3 p.Ala2Pro (c.4G>C) pathogenic?

ACER3 p.Ala2Pro (c.4G>C) is classified Uncertain significance in ACER3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). AlphaMissense: ambiguous (0.4181); Ultra-rare (popmax 0.0469%, sas).

How common is ACER3 p.Ala2Pro (c.4G>C) in the general population?

ACER3 p.Ala2Pro (c.4G>C) is ultra-rare (popmax 0.0469%, sas) (gnomAD).

What do computational predictors say about ACER3 p.Ala2Pro (c.4G>C)?

AlphaMissense predicts ambiguous (score 0.4181) — an in-silico prediction, not a clinical call.

ACER3 p.Ala2Pro

c.4G>C · rs777604778 · VCV1489208

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0469%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4181	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -6.92	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 7.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 39 bp · p 0.037 · regional, not allelic
Overall
CADD	24.2	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 0.0469% South Asian · 39/83,074 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.0028% 43/1,534,792 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0469%	2,130
Remaining individualsnot grpmax-eligible	0.00169%	59,338
European (non-Finnish)	0.000263%	380,426

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: ACER3
Protein: p.Ala2Pro
Coding: c.4G>C
MANE Select: NM_018367
dbSNP: rs777604778
Type: single nucleotide variant
Location: chr11:76860980 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 93.23 · 2 PDB

Full ACER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACER3 p.Ala4Thr Uncertain significance ★★ ⚠ same type
ACER3 p.Arg62Gln Uncertain significance ★★ ⚠ same type
ACER3 p.Gly12Asp Uncertain significance ★★ ⚠ same type
ACER3 p.Ile97Leu Uncertain significance ★★ ⚠ same type
ACER3 p.Val206Ile Uncertain significance ★★ ⚠ same type
ACER3 c.214+19C>G Benign ★★ same type
ACER3 c.320+14A>C Benign ★★ same type
ACER3 c.439-12G>A Benign ★★ 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/acer3-p-ala2pro (accessed [today's date]).

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