Is SDHB p.Ile174Val (c.520A>G) pathogenic?

SDHB p.Ile174Val (c.520A>G) is classified Uncertain significance in SDHB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.0619); Very rare (popmax 0.0011%, sas); Associated with pheochromocytoma/paraganglioma syndrome 4.

What condition is associated with SDHB p.Ile174Val (c.520A>G)?

SDHB p.Ile174Val (c.520A>G) is associated with pheochromocytoma/paraganglioma syndrome 4, pheochromocytoma, gastrointestinal stromal tumor (ClinVar).

How common is SDHB p.Ile174Val (c.520A>G) in the general population?

SDHB p.Ile174Val (c.520A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SDHB p.Ile174Val (c.520A>G)?

AlphaMissense predicts likely benign (score 0.0619) — an in-silico prediction, not a clinical call.

SDHB p.Ile174Val

c.520A>G · rs969943651 · VCV659326

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

pheochromocytoma/paraganglioma syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0619	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.98, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.67 · regional, not allelic
Overall
CADD	16.18	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 0.0011% South Asian · 1/90,820 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000621% 9/1,450,050 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,820
European (non-Finnish)	0.000684%	146,167

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: SDHB
Protein: p.Ile174Val
Coding: c.520A>G
MANE Select: NM_003000
dbSNP: rs969943651
Type: single nucleotide variant
Location: chr1:17027769 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI 0.03 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.14 · 6 PDB
Residue 174: the 'interaction with sdhaf1' region; an α-helix

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

Disease context

pheochromocytoma/paraganglioma syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pheochromocytoma gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

SDHB p.Ile174Thr Uncertain significance ★★ ⚠ same residue
SDHB p.Ile174Met Uncertain significance ★ ⚠ same residue
SDHB c.200+1G>A Pathogenic ★★ same condition
SDHB c.200+1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.200+5G>T Likely pathogenic ★★ same condition
SDHB c.201-1G>C Pathogenic/Likely pathogenic ★★ same condition
SDHB c.201-2A>C Pathogenic ★★ same condition
SDHB c.286+1G>A 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/sdhb-p-ile174val (accessed [today's date]).

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