Is ENPP6 p.Asp41His (c.121G>C) pathogenic?

ENPP6 p.Asp41His (c.121G>C) is classified Uncertain significance in ENPP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely benign (0.2571); Very rare (popmax 0.00333%, amr).

How common is ENPP6 p.Asp41His (c.121G>C) in the general population?

ENPP6 p.Asp41His (c.121G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ENPP6 p.Asp41His (c.121G>C)?

AlphaMissense predicts likely benign (score 0.2571) — an in-silico prediction, not a clinical call.

ENPP6 p.Asp41His

c.121G>C · VCV3508655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2571	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 127 kb · p 0.96 · regional, not allelic
Overall
CADD	21.6	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 0.00333% Admixed American · 2/60,038 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000274% 4/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,019
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-American	0.00133%	75,064

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: ENPP6
Protein: p.Asp41His
Coding: c.121G>C
MANE Select: NM_153343
Type: single nucleotide variant
Location: chr4:184217699 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06

Full ENPP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENPP6 p.Asp41Glu Uncertain significance ★ ⚠ same residue
ENPP6 p.Ser71= Benign ★★ same type
ENPP6 p.Ala20Asp Uncertain significance ★ ⚠ same type
ENPP6 p.Ala20Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala212Thr Uncertain significance ★ ⚠ same type
ENPP6 p.Ala303Pro Uncertain significance ★ ⚠ same type
ENPP6 p.Ala369Gly Uncertain significance ★ ⚠ same type
ENPP6 p.Ala380Pro 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/enpp6-p-asp41his (accessed [today's date]).

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