Is ERMAP p.Pro460Ser (c.1378C>T) pathogenic?

ERMAP p.Pro460Ser (c.1378C>T) is classified Uncertain significance in ERMAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0198%, nfe).

How common is ERMAP p.Pro460Ser (c.1378C>T) in the general population?

ERMAP p.Pro460Ser (c.1378C>T) is ultra-rare (popmax 0.0198%, nfe) (gnomAD).

What do computational predictors say about ERMAP p.Pro460Ser (c.1378C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

ERMAP p.Pro460Ser

c.1378C>T · rs140583376 · VCV2514385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -5.96	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 0.066	GERP -1.7, phastCons 0.085
Regional constraint	o/e 0.93	unconstrained · MANE · 13 kb · p 0.085 · regional, not allelic
Overall
CADD	9.32	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 0.0198% European (non-Finnish) · 233/1,178,528 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.0152% 244/1,610,336 alleles · ultra-rare exomes 235/1,458,062 · genomes 9/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0198%	5,058
Remaining individualsnot grpmax-eligible	0.0112%	8,908
African / African-American	0.00401%	24,955
South Asian	0.00111%	90,322

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: ERMAP
Protein: p.Pro460Ser
Coding: c.1378C>T
MANE Select: NM_001017922
dbSNP: rs140583376
Type: single nucleotide variant
Location: chr1:42843182 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.22
Residue 460: a UniProt-annotated variant site (in sc-3 allele)

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

Similar variants

ERMAP p.Ala4Val Benign ★★ same type
ERMAP p.Arg73= Benign ★★ same type
ERMAP p.Ala157Ser Uncertain significance ★ ⚠ same type
ERMAP p.Ala34Ser Uncertain significance ★ ⚠ same type
ERMAP p.Ala449Ser Uncertain significance ★ ⚠ same type
ERMAP p.Arg117His Uncertain significance ★ ⚠ same type
ERMAP p.Arg231Gly Uncertain significance ★ ⚠ same type
ERMAP p.Arg234Gln 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/ermap-p-pro460ser (accessed [today's date]).

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