Is ERMARD p.Pro180Leu (c.539C>T) pathogenic?

ERMARD p.Pro180Leu (c.539C>T) is classified Uncertain significance in ERMARD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.4405); Very rare (popmax 0.00246%, nfe).

How common is ERMARD p.Pro180Leu (c.539C>T) in the general population?

ERMARD p.Pro180Leu (c.539C>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about ERMARD p.Pro180Leu (c.539C>T)?

AlphaMissense predicts ambiguous (score 0.4405) — an in-silico prediction, not a clinical call.

ERMARD p.Pro180Leu

c.539C>T · rs146333454 · VCV2058500

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4405	ambiguous
REVEL	0.505	indeterminate
SaProt	LLR -11.18	damaging
Splicing
SpliceAI	Δ0.28	acceptor loss, 31 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 30 kb · p 0.34 · regional, not allelic
Overall
CADD	23.8	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 0.00246% European (non-Finnish) · 29/1,179,916 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00217% 35/1,613,760 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)grpmax	0.00246%	40,687
South Asian	0.0022%	45,497

Remaining individuals 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: ERMARD
Protein: p.Pro180Leu
Coding: c.539C>T
MANE Select: NM_018341
dbSNP: rs146333454
Type: single nucleotide variant
Location: chr6:169758999 (GRCh38)
Gene constraint: LOEUF 0.996 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.79

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

Similar variants

ERMARD p.Ala474Val Uncertain significance ★★ ⚠ same type
ERMARD p.Arg367His Uncertain significance ★★ ⚠ same type
ERMARD p.Arg400Ser Uncertain significance ★★ ⚠ same type
ERMARD p.Arg537Gln Uncertain significance ★★ ⚠ same type
ERMARD p.Arg544Cys Uncertain significance ★★ ⚠ same type
ERMARD p.Arg569Cys Uncertain significance ★★ ⚠ same type
ERMARD p.Arg571Gln Uncertain significance ★★ ⚠ same type
ERMARD p.Arg571Trp 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/ermard-p-pro180leu (accessed [today's date]).

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