Is ATF7IP p.Pro998Ser (c.2992C>T) pathogenic?

ATF7IP p.Pro998Ser (c.2992C>T) is classified Uncertain significance in ATF7IP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely benign (0.0858); Ultra-rare (popmax 0.0183%, amr).

How common is ATF7IP p.Pro998Ser (c.2992C>T) in the general population?

ATF7IP p.Pro998Ser (c.2992C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ATF7IP p.Pro998Ser (c.2992C>T)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

ATF7IP p.Pro998Ser

c.2992C>T · VCV3796158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.61, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 37 kb · p 0.12 · regional, not allelic
Overall
CADD	18.52	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 0.0183% Admixed American · 11/59,994 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000805% 13/1,613,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,454
African / African-American	0.00267%	37,454

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: ATF7IP
Protein: p.Pro998Ser
Coding: c.2992C>T
MANE Select: NM_018179
Type: single nucleotide variant
Location: chr12:14478367 (GRCh38)
Gene constraint: LOEUF 0.294 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.39 · 1 PDB
Residue 998: the 'disordered' region

Full ATF7IP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATF7IP p.Ala1069Thr Benign ★★ same type
ATF7IP p.Leu149= Benign ★★ same type
ATF7IP p.Lys530Arg Benign ★★ ⚠ same type
ATF7IP p.Met573Ile Likely benign ★★ same type
ATF7IP p.Ser502Leu Likely benign ★★ same type
ATF7IP p.Ser734Asn Benign ★★ ⚠ same type
ATF7IP c.1559-2A>G Uncertain significance ★ same type
ATF7IP p.Ala1191Val 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/atf7ip-p-pro998ser (accessed [today's date]).

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