Is ENPP4 p.Pro26Arg (c.77C>G) pathogenic?

ENPP4 p.Pro26Arg (c.77C>G) is classified Uncertain significance in ENPP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely benign (0.0926); Very rare (popmax 0.00223%, eas).

How common is ENPP4 p.Pro26Arg (c.77C>G) in the general population?

ENPP4 p.Pro26Arg (c.77C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ENPP4 p.Pro26Arg (c.77C>G)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

ENPP4 p.Pro26Arg

c.77C>G · VCV3844984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -10.61	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Pangolin	Δ0.45	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 706 bp · p 0.0047 · regional, not allelic
Overall
CADD	25.1	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 0.00223% East Asian · 1/44,858 alleles

Overall 0.00143% 23/1,611,014 alleles · very rare exomes 19/1,459,334 · genomes 4/151,680 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0644%	1,553
Remaining individualsnot grpmax-eligible	0.00321%	31,184
East Asiangrpmax	0.00223%	44,858
European (non-Finnish)	8.49e-05%	1,178,012

Ashkenazi Jewish 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: ENPP4
Protein: p.Pro26Arg
Coding: c.77C>G
MANE Select: NM_014936
Type: single nucleotide variant
Location: chr6:46139660 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49 · 2 PDB

Full ENPP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP4 p.Ala181Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Glu Uncertain significance ★ ⚠ same type
ENPP4 p.Ala190Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Gly Uncertain significance ★ ⚠ same type
ENPP4 p.Ala355Ser Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Thr Uncertain significance ★ ⚠ same type
ENPP4 p.Ala409Val Uncertain significance ★ ⚠ same type
ENPP4 p.Ala90Ser 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/enpp4-p-pro26arg (accessed [today's date]).

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