Is ENAM p.Pro422Arg (c.1265C>G) pathogenic?

ENAM p.Pro422Arg (c.1265C>G) is classified Uncertain significance in ENAM (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.128); Very rare (popmax 0.0034%, amr); Associated with amelogenesis imperfecta.

What condition is associated with ENAM p.Pro422Arg (c.1265C>G)?

ENAM p.Pro422Arg (c.1265C>G) is associated with amelogenesis imperfecta (ClinVar).

How common is ENAM p.Pro422Arg (c.1265C>G) in the general population?

ENAM p.Pro422Arg (c.1265C>G) is very rare (popmax 0.0034%, amr) (gnomAD).

How is Amelogenesis imperfecta inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ENAM p.Pro422Arg (c.1265C>G)?

AlphaMissense predicts likely benign (score 0.128) — an in-silico prediction, not a clinical call.

ENAM p.Pro422Arg

c.1265C>G · rs777996409 · VCV904988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0034%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amelogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.128	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -7.31	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 2.2	GERP 1.6, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.57 · regional, not allelic
Overall
CADD	21.4	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 0.0034% Admixed American · 2/58,850 alleles

Filtering AF 0.000564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000249% 4/1,608,520 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0034%	29,425
European (non-Finnish)	0.00017%	589,063

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.Pro422Arg
Coding: c.1265C>G
MANE Select: NM_031889
dbSNP: rs777996409
Type: single nucleotide variant
Location: chr4:70642691 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 36.63
Residue 422: the 'disordered' region

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

Disease context

amelogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amelogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (United States)

Similar variants

ENAM p.Pro422fs Pathogenic/Likely pathogenic ★★ same residue
ENAM c.*69T>A Uncertain significance ★★ same condition
ENAM p.Arg939Lys Uncertain significance ★★ ⚠ same condition
ENAM p.Gly631= Uncertain significance ★★ same condition
ENAM p.Ile552Met Uncertain significance ★★ ⚠ same condition
ENAM p.Lys917Gln Uncertain significance ★★ ⚠ same condition
ENAM p.Pro1093Ser Uncertain significance ★★ ⚠ same condition
ENAM c.-123G>A Benign ★★ 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-pro422arg (accessed [today's date]).

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