Is ENAM p.Pro48Arg (c.143C>G) pathogenic?

ENAM p.Pro48Arg (c.143C>G) is classified Uncertain significance in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: ambiguous (0.4118); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with ENAM p.Pro48Arg (c.143C>G)?

ENAM p.Pro48Arg (c.143C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ENAM p.Pro48Arg (c.143C>G) in the general population?

ENAM p.Pro48Arg (c.143C>G) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ENAM p.Pro48Arg (c.143C>G)?

AlphaMissense predicts ambiguous (score 0.4118) — an in-silico prediction, not a clinical call.

ENAM p.Pro48Arg

c.143C>G · rs762958791 · VCV3088819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4118	ambiguous · top 10% in ENAM
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.32, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.57 · regional, not allelic
Overall
CADD	22.4	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 0.00833% Admixed American · 5/60,004 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,920 alleles · very rare

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: ENAM
Protein: p.Pro48Arg
Coding: c.143C>G
MANE Select: NM_031889
dbSNP: rs762958791
Type: single nucleotide variant
Location: chr4:70631868 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ENAM p.Pro48Ser Uncertain significance ★ ⚠ same residue
ENAM p.Thr758Pro Uncertain significance ★★ ⚠ same condition
ENAM p.Ala72Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala752Ser Uncertain significance ★ ⚠ same condition
ENAM p.Ala790Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala796Thr Uncertain significance ★ ⚠ same condition
ENAM p.Ala798Gly Uncertain significance ★ ⚠ same condition
ENAM p.Ala888Ser Uncertain significance ★ ⚠ same condition

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/enam-p-pro48arg (accessed [today's date]).

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