Is CES4A p.Pro85Leu (c.254C>T) pathogenic?

CES4A p.Pro85Leu (c.254C>T) is classified Uncertain significance in CES4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.3348); Ultra-rare (popmax 0.0111%, eas).

How common is CES4A p.Pro85Leu (c.254C>T) in the general population?

CES4A p.Pro85Leu (c.254C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CES4A p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely benign (score 0.3348) — an in-silico prediction, not a clinical call.

CES4A p.Pro85Leu

c.254C>T · rs376340766 · VCV2233439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3348	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.5, phastCons 0.009
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	18.4	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 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00725% 117/1,613,340 alleles · ultra-rare exomes 112/1,461,128 · genomes 5/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,674
East Asiangrpmax	0.0111%	8,979
Admixed American	0.00833%	11,998
European (non-Finnish)	0.00754%	13,258
South Asian	0.00659%	15,175
African / African-American	0.00133%	74,924

Remaining individuals 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: CES4A
Protein: p.Pro85Leu
Coding: c.254C>T
MANE Select: NM_001364782
dbSNP: rs376340766
Type: single nucleotide variant
Location: chr16:66995823 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.64

Full CES4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES4A p.Ala127Thr Uncertain significance ★ ⚠ same type
CES4A p.Ala158Val Uncertain significance ★ ⚠ same type
CES4A p.Ala185Glu Uncertain significance ★ ⚠ same type
CES4A p.Ala222Glu Uncertain significance ★ ⚠ same type
CES4A p.Ala224Thr Uncertain significance ★ ⚠ same type
CES4A p.Ala236Val Uncertain significance ★ ⚠ same type
CES4A p.Ala250Val Uncertain significance ★ ⚠ same type
CES4A p.Ala271Thr 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/ces4a-p-pro85leu (accessed [today's date]).

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