Is INTS9 p.Phe38Leu (c.114C>G) pathogenic?

INTS9 p.Phe38Leu (c.114C>G) is classified Uncertain significance in INTS9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely pathogenic (0.9992); Ultra-rare (popmax 0.014%, nfe).

How common is INTS9 p.Phe38Leu (c.114C>G) in the general population?

INTS9 p.Phe38Leu (c.114C>G) is ultra-rare (popmax 0.014%, nfe) (gnomAD).

What do computational predictors say about INTS9 p.Phe38Leu (c.114C>G)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

INTS9 p.Phe38Leu

c.114C>G · rs139429194 · VCV2207899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 1% in INTS9
REVEL	0.48	indeterminate
SaProt	LLR -7.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP 0.75, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 93 kb · p 0.36 · regional, not allelic
Overall
CADD	23.2	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 0.014% European (non-Finnish) · 165/1,180,004 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0108% 175/1,614,042 alleles · ultra-rare exomes 166/1,461,836 · genomes 9/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.014%	7,152
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00267%	37,465

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: INTS9
Protein: p.Phe38Leu
Coding: c.114C>G
MANE Select: NM_018250
dbSNP: rs139429194
Type: single nucleotide variant
Location: chr8:28859459 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.95 · 15 PDB

Full INTS9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS9 p.Leu417Pro Uncertain significance ★★ ⚠ same type
INTS9 p.Ala208Val Uncertain significance ★ ⚠ same type
INTS9 p.Ala286Asp Uncertain significance ★ ⚠ same type
INTS9 p.Ala319Val Uncertain significance ★ ⚠ same type
INTS9 p.Ala506Thr Uncertain significance ★ ⚠ same type
INTS9 p.Ala560Thr Uncertain significance ★ ⚠ same type
INTS9 p.Arg401Cys Uncertain significance ★ ⚠ same type
INTS9 p.Arg401His 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/ints9-p-phe38leu (accessed [today's date]).

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