Is CES4A p.Pro514Ser (c.1540C>T) pathogenic?

CES4A p.Pro514Ser (c.1540C>T) is classified Likely benign in CES4A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely benign (0.198); Very rare (popmax 0.00873%, nfe).

How common is CES4A p.Pro514Ser (c.1540C>T) in the general population?

CES4A p.Pro514Ser (c.1540C>T) is very rare (popmax 0.00873%, nfe) (gnomAD).

What do computational predictors say about CES4A p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.198) — an in-silico prediction, not a clinical call.

CES4A p.Pro514Ser

c.1540C>T · rs774279200 · VCV3143250

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.198 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.198	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.89	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 0.55	GERP 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	7.247	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 0.00873% European (non-Finnish) · 103/1,179,914 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00651% 105/1,613,730 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00873%	11,455
African / African-American	0.00267%	37,455

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.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_001364782
dbSNP: rs774279200
Type: single nucleotide variant
Location: chr16:67008996 (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.Pro514Leu Uncertain significance ★ ⚠ same residue
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

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-pro514ser (accessed [today's date]).

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