Is IFRD1 p.Pro403Ser (c.1207C>T) pathogenic?

IFRD1 p.Pro403Ser (c.1207C>T) is classified Uncertain significance in IFRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely benign (0.157); Very rare (popmax 0.00333%, amr).

How common is IFRD1 p.Pro403Ser (c.1207C>T) in the general population?

IFRD1 p.Pro403Ser (c.1207C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about IFRD1 p.Pro403Ser (c.1207C>T)?

AlphaMissense predicts likely benign (score 0.157) — an in-silico prediction, not a clinical call.

IFRD1 p.Pro403Ser

c.1207C>T · rs1307825162 · VCV3108327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.157	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.15 · regional, not allelic
Overall
CADD	26.9	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 0.00333% Admixed American · 2/59,980 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00211% 34/1,612,542 alleles · very rare exomes 30/1,460,390 · genomes 4/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,990
European (non-Finnish)	0.00263%	38,023
Remaining individualsnot grpmax-eligible	0.0016%	62,436

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: IFRD1
Protein: p.Pro403Ser
Coding: c.1207C>T
MANE Select: NM_001550
dbSNP: rs1307825162
Type: single nucleotide variant
Location: chr7:112472802 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.46

Full IFRD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IFRD1 c.619-5A>G Benign ★★ same type
IFRD1 p.Leu212Val Benign ★★ same type
IFRD1 p.Leu71= Benign ★★ same type
IFRD1 p.Ala101Glu Uncertain significance ★ ⚠ same type
IFRD1 p.Ala25Thr Uncertain significance ★ ⚠ same type
IFRD1 p.Ala31Thr Uncertain significance ★ ⚠ same type
IFRD1 p.Ala445Thr Uncertain significance ★ ⚠ same type
IFRD1 p.Ala46Thr 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/ifrd1-p-pro403ser (accessed [today's date]).

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