Is CERS5 p.Leu12Pro (c.35T>C) pathogenic?

CERS5 p.Leu12Pro (c.35T>C) is classified Uncertain significance in CERS5 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1843); Rare (popmax 0.101%, mid).

How common is CERS5 p.Leu12Pro (c.35T>C) in the general population?

CERS5 p.Leu12Pro (c.35T>C) is rare (popmax 0.101%, mid) (gnomAD).

What do computational predictors say about CERS5 p.Leu12Pro (c.35T>C)?

AlphaMissense predicts likely benign (score 0.1843) — an in-silico prediction, not a clinical call.

CERS5 p.Leu12Pro

c.35T>C · rs199600749 · VCV1048828

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1843 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1843	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -13.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 33 kb · p 0.004 · regional, not allelic
Overall
CADD	24.4	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 0.101% Middle Eastern · 6/5,922 alleles

Filtering AF 0.044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0301%

Overall 0.0256% 406/1,586,910 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.101%	987
European (non-Finnish)	0.0294%	3,405
Remaining individualsnot grpmax-eligible	0.0261%	3,828
Admixed American	0.0234%	4,265
South Asian	0.0201%	4,964
African / African-American	0.0126%	7,910

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.Leu12Pro
Coding: c.35T>C
MANE Select: NM_147190
dbSNP: rs199600749
Type: single nucleotide variant
Location: chr12:50167263 (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.Ala2Thr 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

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-leu12pro (accessed [today's date]).

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