Is MIF p.Pro2Arg (c.5C>G) pathogenic?

MIF p.Pro2Arg (c.5C>G) is classified Uncertain significance in MIF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.9636); Ultra-rare (popmax 0.0115%, nfe).

How common is MIF p.Pro2Arg (c.5C>G) in the general population?

MIF p.Pro2Arg (c.5C>G) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about MIF p.Pro2Arg (c.5C>G)?

AlphaMissense predicts likely pathogenic (score 0.9636) — an in-silico prediction, not a clinical call.

MIF p.Pro2Arg

c.5C>G · rs200500959 · VCV2652976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9636	likely pathogenic · top 7% in MIF
REVEL	0.733	pathogenic-leaning
SaProt	LLR -15.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.66, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0115% European (non-Finnish) · 136/1,179,480 alleles

Filtering AF 0.00995% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00874% 141/1,612,762 alleles · ultra-rare exomes 136/1,460,434 · genomes 5/152,328 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,673
Admixed American	0.00333%	30,005
African / African-American	0.00267%	37,509
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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: MIF
Protein: p.Pro2Arg
Coding: c.5C>G
MANE Select: NM_002415
dbSNP: rs200500959
Type: single nucleotide variant
Location: chr22:23894479 (GRCh38)
Gene constraint: LOEUF 1.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.60 · 119 PDB
Residue 2: an active site

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

Similar variants

MIF p.Ala58Thr Uncertain significance ★★ ⚠ same type
MIF p.Ala28Thr Uncertain significance ★ same type
MIF p.Ala28Val Uncertain significance ★ same type
MIF p.Ala71Pro Uncertain significance ★ ⚠ same type
MIF p.Arg74Gly Uncertain significance ★ ⚠ same type
MIF p.Arg74Leu Uncertain significance ★ ⚠ same type
MIF p.Asn111Thr Uncertain significance ★ ⚠ same type
MIF p.Gly52Cys 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/mif-p-pro2arg (accessed [today's date]).

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