Is IFIH1 p.Pro765Ser (c.2293C>T) pathogenic?

IFIH1 p.Pro765Ser (c.2293C>T) is classified Likely benign in IFIH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely benign (0.3021); Very rare (popmax 0.00223%, eas); Associated with Aicardi-Goutieres syndrome 7.

What condition is associated with IFIH1 p.Pro765Ser (c.2293C>T)?

IFIH1 p.Pro765Ser (c.2293C>T) is associated with Aicardi-Goutieres syndrome 7, Singleton-Merten syndrome 1 (ClinVar).

How common is IFIH1 p.Pro765Ser (c.2293C>T) in the general population?

IFIH1 p.Pro765Ser (c.2293C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

What do computational predictors say about IFIH1 p.Pro765Ser (c.2293C>T)?

AlphaMissense predicts likely benign (score 0.3021) — an in-silico prediction, not a clinical call.

IFIH1 p.Pro765Ser

c.2293C>T · rs1474738840 · VCV1479376

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 7

Computational evidence

Protein change
AlphaMissense	0.3021	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -6.41	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 51 kb · p 0.00062 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Overall 6.2e-05% 1/1,613,084 alleles · very rare exomes 0/1,460,886 · genomes 1/152,198 · joint denominator

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.Pro765Ser
Coding: c.2293C>T
MANE Select: NM_022168
dbSNP: rs1474738840
Type: single nucleotide variant
Location: chr2:162276698 (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.Pro765= Likely benign ★★ same residue
IFIH1 p.Pro765Leu 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-pro765ser (accessed [today's date]).

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