Is CERS3 p.Thr4= (c.12G>A) pathogenic?

CERS3 p.Thr4= (c.12G>A) is classified Benign in CERS3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 7.46%, nfe) — too common for a highly-penetrant pathogenic allele.

CERS3 p.Thr4=

Q: How common is CERS3 p.Thr4= (c.12G>A) in the general population?

CERS3 p.Thr4= (c.12G>A) is common (popmax 7.46%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.12G>A · rs77089459 · VCV1270495

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 7.46%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.2	GERP -3.7
Overall
CADD	0.719	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.46% European (non-Finnish) · 87,925/1,179,360 alleles

Filtering AF 7.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.4%

Overall 6.37% 102,699/1,613,254 alleles · common exomes 95,638/1,460,998 · genomes 7,061/152,256 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	8.67%	12
European (non-Finnish)grpmax	7.46%	13
Amishnot grpmax-eligible	6.8%	15
Remaining individualsnot grpmax-eligible	5.44%	18
Ashkenazi Jewishnot grpmax-eligible	3.84%	26
South Asian	2.69%	37
Admixed American	2.28%	44
Middle Eastern	0.957%	104
African / African-American	0.957%	104
East Asian	0.0936%	1,069

Finnish 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: CERS3
Protein: p.Thr4=
Coding: c.12G>A
MANE Select: NM_001378789
dbSNP: rs77089459
Type: single nucleotide variant
Location: chr15:100501838 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.52

Full CERS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CERS3 p.Thr4Met Likely benign ★ same residue
CERS3 c.466-1G>T Likely pathogenic ★★ same type
CERS3 p.Arg75Ter Likely pathogenic ★★ same type
CERS3 p.Arg275Cys Uncertain significance ★★ ⚠ same type
CERS3 p.Ser177Phe Uncertain significance ★★ ⚠ same type
CERS3 c.174-81G>A Benign ★★ same type
CERS3 c.407+74C>T Benign ★★ same type
CERS3 c.465+65A>T 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/cers3-p-thr4 (accessed [today's date]).

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