Is CES5A p.Pro139Arg (c.416C>G) pathogenic?

CES5A p.Pro139Arg (c.416C>G) is classified Uncertain significance in CES5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: ambiguous (0.5506); Ultra-rare (popmax 0.031%, nfe).

How common is CES5A p.Pro139Arg (c.416C>G) in the general population?

CES5A p.Pro139Arg (c.416C>G) is ultra-rare (popmax 0.031%, nfe) (gnomAD).

What do computational predictors say about CES5A p.Pro139Arg (c.416C>G)?

AlphaMissense predicts ambiguous (score 0.5506) — an in-silico prediction, not a clinical call.

CES5A p.Pro139Arg

c.416C>G · rs199716261 · VCV2364504

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5506 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.031%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5506	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -13.08	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	23.0	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 0.031% European (non-Finnish) · 366/1,180,000 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.0247% 399/1,613,924 alleles · ultra-rare exomes 375/1,461,726 · genomes 24/152,198 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.048%	2,083
European (non-Finnish)grpmax	0.031%	3,224
African / African-American	0.004%	24,973

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: CES5A
Protein: p.Pro139Arg
Coding: c.416C>G
MANE Select: NM_001143685
dbSNP: rs199716261
Type: single nucleotide variant
Location: chr16:55871626 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.48

Full CES5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES5A p.Leu527= Benign ★★ same type
CES5A p.Ala154Gly Uncertain significance ★ ⚠ same type
CES5A p.Ala195Val Uncertain significance ★ ⚠ same type
CES5A p.Ala262Thr Uncertain significance ★ ⚠ same type
CES5A p.Ala282Val Uncertain significance ★ ⚠ same type
CES5A p.Ala334Thr Uncertain significance ★ ⚠ same type
CES5A p.Ala465Gly Uncertain significance ★ ⚠ same type
CES5A p.Ala465Pro 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/ces5a-p-pro139arg (accessed [today's date]).

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