Is ENKUR p.Pro25Ser (c.73C>T) pathogenic?

ENKUR p.Pro25Ser (c.73C>T) is classified Uncertain significance in ENKUR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.0954); Very rare (popmax 0.00366%, nfe).

How common is ENKUR p.Pro25Ser (c.73C>T) in the general population?

ENKUR p.Pro25Ser (c.73C>T) is very rare (popmax 0.00366%, nfe) (gnomAD).

What do computational predictors say about ENKUR p.Pro25Ser (c.73C>T)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

ENKUR p.Pro25Ser

c.73C>T · VCV3844906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00366%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -5.67	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 5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.93 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00366% European (non-Finnish) · 43/1,174,674 alleles

Filtering AF 0.00276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.00293% 47/1,603,210 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00366%	27,318
Admixed American	0.0034%	29,383
Remaining individualsnot grpmax-eligible	0.00161%	62,068
African / African-American	0.00134%	74,606

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: ENKUR
Protein: p.Pro25Ser
Coding: c.73C>T
MANE Select: NM_145010
Type: single nucleotide variant
Location: chr10:25015864 (GRCh38)
Gene constraint: LOEUF 0.98 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.24 · 2 PDB

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

Similar variants

THNSL1 p.Thr25Met Uncertain significance ★ ⚠ same residue
ENKUR p.Gly140Glu Uncertain significance ★★ ⚠ same type
ENKUR p.Arg161Gln Uncertain significance ★ ⚠ same type
ENKUR p.Arg174Gly Uncertain significance ★ ⚠ same type
ENKUR p.Arg174Pro Uncertain significance ★ ⚠ same type
ENKUR p.Arg226Cys Uncertain significance ★ ⚠ same type
ENKUR p.Arg80Gln Uncertain significance ★ ⚠ same type
ENKUR p.Asn12Asp 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/enkur-p-pro25ser (accessed [today's date]).

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