Is CERS5 p.Phe67Leu (c.199T>C) pathogenic?

CERS5 p.Phe67Leu (c.199T>C) is classified Uncertain significance in CERS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely pathogenic (0.6996); Ultra-rare (popmax 0.0457%, afr).

How common is CERS5 p.Phe67Leu (c.199T>C) in the general population?

CERS5 p.Phe67Leu (c.199T>C) is ultra-rare (popmax 0.0457%, afr) (gnomAD).

What do computational predictors say about CERS5 p.Phe67Leu (c.199T>C)?

AlphaMissense predicts likely pathogenic (score 0.6996) — an in-silico prediction, not a clinical call.

CERS5 p.Phe67Leu

c.199T>C · rs139125396 · VCV3143176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0457%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6996	likely pathogenic
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 33 kb · p 0.004 · regional, not allelic
Overall
CADD	22.6	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 0.0457% African / African-American · 34/74,402 alleles

Filtering AF 0.0336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00258% 41/1,591,384 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0457%	2,188
Admixed American	0.00834%	11,993
Remaining individualsnot grpmax-eligible	0.00162%	61,608
South Asian	0.00111%	90,484

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.Phe67Leu
Coding: c.199T>C
MANE Select: NM_147190
dbSNP: rs139125396
Type: single nucleotide variant
Location: chr12:50144056 (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-phe67leu (accessed [today's date]).

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