Is ERVFRD-1 p.Pro181Ser (c.541C>T) pathogenic?

ERVFRD-1 p.Pro181Ser (c.541C>T) is classified Uncertain significance in ERVFRD-1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1472); Very rare (popmax 0.00666%, amr).

How common is ERVFRD-1 p.Pro181Ser (c.541C>T) in the general population?

ERVFRD-1 p.Pro181Ser (c.541C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about ERVFRD-1 p.Pro181Ser (c.541C>T)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

ERVFRD-1 p.Pro181Ser

c.541C>T · VCV4250979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.68	phastCons 0.85
Regional constraint	o/e 0.86	unconstrained · MANE · 1,613 bp · p 0.00043 · regional, not allelic
Overall
CADD	10.78	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 0.00666% Admixed American · 4/60,026 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,614,198 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	8.47e-05%	1,180,030

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: ERVFRD-1
Protein: p.Pro181Ser
Coding: c.541C>T
MANE Select: NM_001135575 · reported on NM_207582
Type: single nucleotide variant
Location: chr6:11104770 (GRCh38)

Full ERVFRD-1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/ervfrd-1-p-pro181ser (accessed [today's date]).

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