Is QRFPR p.Val176Ile (c.526G>A) pathogenic?

QRFPR p.Val176Ile (c.526G>A) is classified Uncertain significance in QRFPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00891%, eas).

How common is QRFPR p.Val176Ile (c.526G>A) in the general population?

QRFPR p.Val176Ile (c.526G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about QRFPR p.Val176Ile (c.526G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

QRFPR p.Val176Ile

c.526G>A · VCV4148858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.81	GERP 0.053
Regional constraint	o/e 1.02	unconstrained · MANE · 51 kb · p 0.68 · regional, not allelic
Overall
CADD	14.87	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 0.00891% East Asian · 4/44,870 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00204% 33/1,614,044 alleles · very rare exomes 25/1,461,742 · genomes 8/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
African / African-American	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.0017%	58,996
Admixed American	0.00167%	60,028
South Asian	0.0011%	91,080

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: QRFPR
Protein: p.Val176Ile
Coding: c.526G>A
MANE Select: NM_198179
Type: single nucleotide variant
Location: chr4:121336842 (GRCh38)
Gene constraint: LOEUF 1.532 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.74 · 2 PDB
Residue 176: an α-helix

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

Similar variants

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QRFPR p.Ala315Val Uncertain significance ★ ⚠ same type
QRFPR p.Arg13Trp Uncertain significance ★ ⚠ same type
QRFPR p.Arg160Gln Uncertain significance ★ ⚠ same type
QRFPR p.Arg161Thr Uncertain significance ★ ⚠ same type
QRFPR p.Arg16Pro Uncertain significance ★ same type
QRFPR p.Arg22Gln 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/qrfpr-p-val176ile (accessed [today's date]).

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