Is CYTH4 p.Met74Val (c.220A>G) pathogenic?

CYTH4 p.Met74Val (c.220A>G) is classified Benign in CYTH4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-05). AlphaMissense: likely benign (0.1689); Common (popmax 7.04%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CYTH4 p.Met74Val (c.220A>G)?

AlphaMissense predicts likely benign (score 0.1689) — an in-silico prediction, not a clinical call.

CYTH4 p.Met74Val

Q: How common is CYTH4 p.Met74Val (c.220A>G) in the general population?

CYTH4 p.Met74Val (c.220A>G) is common (popmax 7.04%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.220A>G · rs16998061 · VCV781618

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1689 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.04%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1689	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 0.94, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 31 kb · p 5.9e-07 · regional, not allelic
Overall
CADD	21.8	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 7.04% African / African-American · 5,283/74,998 alleles

Filtering AF 6.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.82%

Overall 0.371% 5,992/1,613,002 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.04%	14
Admixed American	0.489%	205
Remaining individualsnot grpmax-eligible	0.363%	275
Middle Eastern	0.066%	1,514
European (non-Finnish)	0.0149%	6,701
South Asian	0.00991%	10,090

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: CYTH4
Protein: p.Met74Val
Coding: c.220A>G
MANE Select: NM_013385
dbSNP: rs16998061
Type: single nucleotide variant
Location: chr22:37296051 (GRCh38)
Gene constraint: LOEUF 0.516 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 87.17
Residue 74: the sec7 domain; a UniProt-annotated variant site (in)

Full CYTH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYTH4 p.Asn107His Benign ★★ ⚠ same type
CYTH4 p.Leu88= Benign ★★ same type
CYTH4 p.Ala136Thr Uncertain significance ★ ⚠ same type
CYTH4 p.Ala166Val Uncertain significance ★ ⚠ same type
CYTH4 p.Ala9Glu Uncertain significance ★ ⚠ same type
CYTH4 p.Arg205Gln Uncertain significance ★ ⚠ same type
CYTH4 p.Arg212Cys Uncertain significance ★ ⚠ same type
CYTH4 p.Arg218Cys 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/cyth4-p-met74val (accessed [today's date]).

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