Is CERS5 p.Ala2Thr (c.4G>A) pathogenic?

CERS5 p.Ala2Thr (c.4G>A) is classified Uncertain significance in CERS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.2884); Very rare (popmax 0.000176%, nfe).

How common is CERS5 p.Ala2Thr (c.4G>A) in the general population?

CERS5 p.Ala2Thr (c.4G>A) is very rare (popmax 0.000176%, nfe) (gnomAD).

What do computational predictors say about CERS5 p.Ala2Thr (c.4G>A)?

AlphaMissense predicts likely benign (score 0.2884) — an in-silico prediction, not a clinical call.

CERS5 p.Ala2Thr

c.4G>A · VCV3266339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000176%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2884	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -8.48	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 5.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 33 kb · p 0.004 · regional, not allelic
Overall
CADD	24.1	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 0.000176% European (non-Finnish) · 2/1,136,260 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000147% 2/1,357,342 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: CERS5
Protein: p.Ala2Thr
Coding: c.4G>A
MANE Select: NM_147190
Type: single nucleotide variant
Location: chr12:50167294 (GRCh38)
Gene constraint: LOEUF 0.981 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91

Full CERS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS5 p.Ala278Val Uncertain significance ★ ⚠ same type
CERS5 p.Ala338Ser Uncertain significance ★ ⚠ same type
CERS5 p.Ala377Thr Uncertain significance ★ ⚠ same type
CERS5 p.Arg127His Uncertain significance ★ ⚠ same type
CERS5 p.Arg238Gln Uncertain significance ★ ⚠ same type
CERS5 p.Arg267Gln Uncertain significance ★ ⚠ same type
CERS5 p.Arg284Gln Uncertain significance ★ ⚠ same type
CERS5 p.Arg349Cys 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/cers5-p-ala2thr (accessed [today's date]).

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