Is ACER3 p.Val52Ile (c.154G>A) pathogenic?

ACER3 p.Val52Ile (c.154G>A) is classified Benign in ACER3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.063); Common (popmax 74.1%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ACER3 p.Val52Ile (c.154G>A)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

ACER3 p.Val52Ile

Q: How common is ACER3 p.Val52Ile (c.154G>A) in the general population?

ACER3 p.Val52Ile (c.154G>A) is common (popmax 74.1%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.154G>A · rs4379869 · VCV1165287

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 74.1%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -4.90	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 2.9	GERP -0.72, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 159 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	4.95	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 74.1% European (non-Finnish) · 864,980/1,167,340 alleles

Filtering AF 74% ClinGen BA1/BS1 input FAF95, joint · FAF99 73.9%

Overall 71.5% 1,143,254/1,598,032 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	78.9%	1
Ashkenazi Jewishnot grpmax-eligible	74.9%	1
European (non-Finnish)grpmax	74.1%	1
Finnishnot grpmax-eligible	71%	1
Remaining individualsnot grpmax-eligible	70.4%	1
Middle Eastern	69.5%	1
South Asian	63.7%	2
East Asian	63.6%	2
African / African-American	63.2%	2
Admixed American	49.7%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val52Ile
Coding: c.154G>A
MANE Select: NM_018367
dbSNP: rs4379869
Type: single nucleotide variant
Location: chr11:76926607 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI 0.30 (gnomAD)
Structure: AlphaFold pLDDT 93.23 · 2 PDB
Residue 52: an α-helix

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

Similar variants

ACER3 p.Ala2Pro Uncertain significance ★★ ⚠ same type
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

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-val52ile (accessed [today's date]).

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