Is BORCS8 p.Val74Met (c.220G>A) pathogenic?

BORCS8 p.Val74Met (c.220G>A) is classified Uncertain significance in BORCS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: likely benign (0.2172); Ultra-rare (popmax 0.0166%, mid).

How common is BORCS8 p.Val74Met (c.220G>A) in the general population?

BORCS8 p.Val74Met (c.220G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about BORCS8 p.Val74Met (c.220G>A)?

AlphaMissense predicts likely benign (score 0.2172) — an in-silico prediction, not a clinical call.

BORCS8 p.Val74Met

c.220G>A · rs369618700 · VCV2299127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2172	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -7.70	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 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.96 · regional, not allelic
Overall
CADD	25.0	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 0.0166% Middle Eastern · 1/6,014 alleles

Filtering AF 0.000455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000322%

Overall 0.00103% 16/1,549,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,014
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,632
Remaining individualsnot grpmax-eligible	0.00333%	30,021
African / African-American	0.00274%	36,491
European (non-Finnish)	0.000872%	114,656

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: BORCS8
Protein: p.Val74Met
Coding: c.220G>A
MANE Select: NM_001145784
dbSNP: rs369618700
Type: single nucleotide variant
Location: chr19:19182679 (GRCh38)
Gene constraint: LOEUF 1.104 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.74

Full BORCS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BORCS8 p.Glu68Ter Likely pathogenic ★ same type
BORCS8 p.Ala25Gly Uncertain significance ★ ⚠ same type
BORCS8 p.Arg40His Uncertain significance ★ ⚠ same type
BORCS8 p.Arg55Cys Uncertain significance ★ ⚠ same type
BORCS8 p.Arg55Leu Uncertain significance ★ ⚠ same type
BORCS8 p.Arg85His Uncertain significance ★ ⚠ same type
BORCS8 p.Arg85Leu Uncertain significance ★ ⚠ same type
BORCS8 p.Arg98Trp 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/borcs8-p-val74met (accessed [today's date]).

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