Is ACER2 p.Pro208Ser (c.622C>T) pathogenic?

ACER2 p.Pro208Ser (c.622C>T) is classified Uncertain significance in ACER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: ambiguous (0.4614); Absent from gnomAD v4.1.

How common is ACER2 p.Pro208Ser (c.622C>T) in the general population?

ACER2 p.Pro208Ser (c.622C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACER2 p.Pro208Ser (c.622C>T)?

AlphaMissense predicts ambiguous (score 0.4614) — an in-silico prediction, not a clinical call.

ACER2 p.Pro208Ser

c.622C>T · VCV3998191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4614 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4614	ambiguous
REVEL	0.469	indeterminate
SaProt	LLR -8.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 42 kb · p 0.55 · regional, not allelic
Overall
CADD	27.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACER2
Protein: p.Pro208Ser
Coding: c.622C>T
MANE Select: NM_001010887
Type: single nucleotide variant
Location: chr9:19446399 (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.Pro208Leu Uncertain significance ★ ⚠ same residue
ACER2 p.Arg112Lys Uncertain significance ★ ⚠ same type
ACER2 p.Arg112Ser Uncertain significance ★ ⚠ same type
ACER2 p.Arg119Pro 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

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-pro208ser (accessed [today's date]).

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