Is CERS2 p.Arg75Gln (c.224G>A) pathogenic?

CERS2 p.Arg75Gln (c.224G>A) is classified Uncertain significance in CERS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely benign (0.2395); Very rare (popmax 0.0022%, nfe).

How common is CERS2 p.Arg75Gln (c.224G>A) in the general population?

CERS2 p.Arg75Gln (c.224G>A) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about CERS2 p.Arg75Gln (c.224G>A)?

AlphaMissense predicts likely benign (score 0.2395) — an in-silico prediction, not a clinical call.

CERS2 p.Arg75Gln

c.224G>A · VCV4001277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2395	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -9.68	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 1,991 bp · p 3.1e-05 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,180,044 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00167% 27/1,614,042 alleles · very rare exomes 23/1,461,884 · genomes 4/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,386
South Asian	0.0011%	91,086

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: CERS2
Protein: p.Arg75Gln
Coding: c.224G>A
MANE Select: NM_022075
Type: single nucleotide variant
Location: chr1:150968462 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 87.31
Residue 75: the 'homeobox-like' region

Full CERS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS2 p.Ala152= Benign ★★ same type
CERS2 p.Ser199= Benign ★★ same type
CERS2 p.Tyr254= Benign ★★ same type
CERS2 p.Ala23Ser Uncertain significance ★ ⚠ same type
CERS2 p.Ala23Val Uncertain significance ★ ⚠ same type
CERS2 p.Ala34Thr Uncertain significance ★ same type
CERS2 p.Ala46Gly Uncertain significance ★ ⚠ same type
CERS2 p.Arg105Leu 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/cers2-p-arg75gln (accessed [today's date]).

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