Is CES4A p.Pro60Ala (c.178C>G) pathogenic?

CES4A p.Pro60Ala (c.178C>G) is classified Uncertain significance in CES4A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: ambiguous (0.4732); Ultra-rare (popmax 0.0878%, sas).

How common is CES4A p.Pro60Ala (c.178C>G) in the general population?

CES4A p.Pro60Ala (c.178C>G) is ultra-rare (popmax 0.0878%, sas) (gnomAD).

What do computational predictors say about CES4A p.Pro60Ala (c.178C>G)?

AlphaMissense predicts ambiguous (score 0.4732) — an in-silico prediction, not a clinical call.

CES4A p.Pro60Ala

c.178C>G · rs772475063 · VCV2459338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0878%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4732	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -12.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 2.6, phastCons 0.05
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	22.3	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 0.0878% South Asian · 80/91,090 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0666%

Overall 0.00514% 83/1,614,242 alleles · ultra-rare exomes 83/1,461,884 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0878%	1,139
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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.Pro60Ala
Coding: c.178C>G
MANE Select: NM_001364782
dbSNP: rs772475063
Type: single nucleotide variant
Location: chr16:66995747 (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-pro60ala (accessed [today's date]).

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