Is ERVV-2 p.Thr208Pro (c.622A>C) pathogenic?

ERVV-2 p.Thr208Pro (c.622A>C) is classified Uncertain significance in ERVV-2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.00687%, afr).

How common is ERVV-2 p.Thr208Pro (c.622A>C) in the general population?

ERVV-2 p.Thr208Pro (c.622A>C) is very rare (popmax 0.00687%, afr) (gnomAD).

What do computational predictors say about ERVV-2 p.Thr208Pro (c.622A>C)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

ERVV-2 p.Thr208Pro

c.622A>C · VCV4665317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP 0.2
Regional constraint	o/e 0.22	constrained · MANE · 274 bp · p 5e-17 · regional, not allelic
Overall
CADD	1.255	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 0.00687% African / African-American · 5/72,736 alleles

Filtering AF 0.00271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.000391% 6/1,534,544 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00687%	14,547
Remaining individualsnot grpmax-eligible	0.00167%	59,946

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: ERVV-2
Protein: p.Thr208Pro
Coding: c.622A>C
MANE Select: NM_001191055
Type: single nucleotide variant
Location: chr19:53049873 (GRCh38)
Gene constraint: LOEUF 1.451 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 46.18

Full ERVV-2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERVV-2 p.Ala337Thr Uncertain significance ★ ⚠ same type
ERVV-2 p.Ala442Ser Uncertain significance ★ ⚠ same type
ERVV-2 p.Ala450Thr Uncertain significance ★ ⚠ same type
ERVV-2 p.Arg195Ser Uncertain significance ★ ⚠ same type
ERVV-2 p.Arg304Gln Uncertain significance ★ ⚠ same type
ERVV-2 p.Arg304Gly Uncertain significance ★ ⚠ same type
ERVV-2 p.Arg441Gly Uncertain significance ★ ⚠ same type
ERVV-2 p.Arg441Lys 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/ervv-2-p-thr208pro (accessed [today's date]).

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