Is IFIH1 p.Pro765= (c.2295C>A) pathogenic?

IFIH1 p.Pro765= (c.2295C>A) is classified Likely benign in IFIH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0238%, amr); Associated with Aicardi-Goutieres syndrome 7.

What condition is associated with IFIH1 p.Pro765= (c.2295C>A)?

IFIH1 p.Pro765= (c.2295C>A) is associated with Aicardi-Goutieres syndrome 7, Singleton-Merten syndrome 1 (ClinVar).

How common is IFIH1 p.Pro765= (c.2295C>A) in the general population?

IFIH1 p.Pro765= (c.2295C>A) is ultra-rare (popmax 0.0238%, amr) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

IFIH1 p.Pro765=

c.2295C>A · rs769746385 · VCV703823

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, amr)

Conditions

Aicardi-Goutieres syndrome 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.56	GERP -3.8, phastCons 0.99
Overall
CADD	3.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0238% Admixed American · 14/58,840 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00342% 55/1,609,544 alleles · ultra-rare exomes 47/1,457,344 · genomes 8/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0238%	4,203
Remaining individualsnot grpmax-eligible	0.00643%	15,563
European (non-Finnish)	0.00314%	31,854

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: IFIH1
Protein: p.Pro765=
Coding: c.2295C>A
MANE Select: NM_022168
dbSNP: rs769746385
Type: single nucleotide variant
Location: chr2:162276696 (GRCh38)
Gene constraint: LOEUF 1.406 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.16 · 13 PDB
Residue 765: the helicase c-terminal domain

Full IFIH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Singleton-Merten syndrome 1

For Aicardi-Goutières syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

IFIH1 p.Pro765Leu Likely benign ★★ ⚠ same residue
IFIH1 p.Pro765Ser Likely benign ★ same residue
IFIH1 p.Pro765Thr Uncertain significance ★ ⚠ same residue
IFIH1 p.Arg720Gln Pathogenic ★★ ⚠ same condition
IFIH1 p.Arg779Cys Pathogenic ★★ ⚠ same condition
IFIH1 p.Arg779His Pathogenic/Likely pathogenic ★★ ⚠ same condition
IFIH1 p.Arg779Leu Pathogenic/Likely pathogenic ★★ same condition
IFIH1 p.Arg822Gln Pathogenic/Likely pathogenic ★★ same condition

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/ifih1-p-pro765 (accessed [today's date]).

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