Is QRFPR p.Ile232Ser (c.695T>G) pathogenic?

QRFPR p.Ile232Ser (c.695T>G) is classified Uncertain significance in QRFPR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.1261); Ultra-rare (popmax 0.0927%, nfe).

How common is QRFPR p.Ile232Ser (c.695T>G) in the general population?

QRFPR p.Ile232Ser (c.695T>G) is ultra-rare (popmax 0.0927%, nfe) (gnomAD).

What do computational predictors say about QRFPR p.Ile232Ser (c.695T>G)?

AlphaMissense predicts likely benign (score 0.1261) — an in-silico prediction, not a clinical call.

QRFPR p.Ile232Ser

c.695T>G · rs139457842 · VCV2347229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1261 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0927%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1261	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -0.4, phastCons 0.031
Regional constraint	o/e 1.02	unconstrained · MANE · 51 kb · p 0.68 · regional, not allelic
Overall
CADD	15.38	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 0.0927% European (non-Finnish) · 1,094/1,179,986 alleles

Filtering AF 0.0881% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0863%

Overall 0.072% 1,162/1,614,148 alleles · ultra-rare exomes 1,094/1,461,804 · genomes 68/152,344 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0927%	1,079
Remaining individualsnot grpmax-eligible	0.0592%	1,689
Middle Eastern	0.0495%	2,021
African / African-American	0.02%	5,003
Finnishnot grpmax-eligible	0.0109%	9,149
Admixed American	0.00666%	15,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	91,082

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.Ile232Ser
Coding: c.695T>G
MANE Select: NM_198179
dbSNP: rs139457842
Type: single nucleotide variant
Location: chr4:121332923 (GRCh38)
Gene constraint: LOEUF 1.532 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.74 · 2 PDB
Residue 232: an α-helix

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

Similar variants

QRFPR p.Ile296Thr Uncertain significance ★★ ⚠ same type
QRFPR p.Ala128Thr Uncertain significance ★ ⚠ same type
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-ile232ser (accessed [today's date]).

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