Is ERVFRD-1 p.Pro175Ser (c.523C>T) pathogenic?

ERVFRD-1 p.Pro175Ser (c.523C>T) is classified Uncertain significance in ERVFRD-1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely benign (0.2373); Rare (popmax 0.12%, sas).

How common is ERVFRD-1 p.Pro175Ser (c.523C>T) in the general population?

ERVFRD-1 p.Pro175Ser (c.523C>T) is rare (popmax 0.12%, sas) (gnomAD).

What do computational predictors say about ERVFRD-1 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.2373) — an in-silico prediction, not a clinical call.

ERVFRD-1 p.Pro175Ser

c.523C>T · rs543348563 · VCV2257666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2373 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2373	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.36	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 0.68	phastCons 0.97
Regional constraint	o/e 0.86	unconstrained · MANE · 1,613 bp · p 0.00043 · regional, not allelic
Overall
CADD	19.94	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 0.12% South Asian · 109/91,084 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0946%

Overall 0.007% 113/1,614,226 alleles · rare exomes 108/1,461,884 · genomes 5/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	836
Remaining individualsnot grpmax-eligible	0.0032%	31,256
African / African-American	0.00133%	75,066
European (non-Finnish)	8.47e-05%	1,180,038

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.Pro175Ser
Coding: c.523C>T
MANE Select: NM_207582
dbSNP: rs543348563
Type: single nucleotide variant
Location: chr6:11104788 (GRCh38)
Gene constraint: LOEUF 0.957 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.71 · 3 PDB

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

Similar variants

ERVFRD-1 p.Ala15Val Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Ala210Gly Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Ala225Val Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Ala70Val Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Arg104Cys Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Arg104His Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Arg18His Uncertain significance ★ ⚠ same type
ERVFRD-1 p.Arg191Trp 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/ervfrd-1-p-pro175ser (accessed [today's date]).

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